ES2539365T3 - 2-aminoindole compounds and methods for the treatment of malaria - Google Patents

Abstract

A compound of formula IIa: ** Formula ** or a pharmaceutically acceptable salt thereof, in which: X is carbon or nitrogen; Y is carbon or nitrogen; R1a is hydrogen, halogen, nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl ( C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R5a) 2, C (> = NOH) NH2, NR5aCON (R5a ) 2, CON (R5a) 2, CO2R5a, COR6a, OC (O) R5a, SO2N (R5a) 2, SO2R6a, NR5aCOR6a, NR5aCO2R6a, NR5aSO2R6a or OC (> = O) N (R5a) 2, each optionally substituted with one or more groups represented by R4a; R2a is (C1-C6) alkyl, (C1-C6) alkoxy, S-C1-C6 alkyl, SO-C1-C6 alkyl or SO2-C1-C6 alkyl, optionally substituted with one or more groups represented by R4a; R3a is halogen, (C1-C6) alkyl or (C1-C6) alkoxy, each optionally substituted with one or more groups represented by R4a; each R4a is independently halogen, nitro, cyano, hydroxy, (C1-C4) alkyl, halo (C1-C3) alkyl, hydroxyalkyl (C1-C4), alkoxy (C1-C4), haloalkoxy (C1-C4), aryl, haloaryl , cycloalkyl, arylalkyl (C1-C3), arylalkoxy (C1-C4), heterocyclyl, N (R5a) 2, C (> = NOH) NH2, NR5aCON (R5a) 2, CON (R5a) 2, CO2R5a, COR6a, OC (O) R5a, SO2N (R5a) 2, SO2R6a, SR6a, S-(C1-C3) alkylcycloalkyl, NR5aCOR6a, NR5CO2R6a, NR5aSO2R6a, S (> = O) R6a, -Ocycloalkyl, -O-heterocyclyl, ada OC (> = O) N (R5a) 2, each R5a is independently hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C6) alkyl, each optionally substituted with halogen, (C1-C3) alkoxy, alkyl ( C1-C3), haloalkyl (C1-C3), haloalkoxy (C1-C3), cyano or nitro; and each R6a is independently hydrogen, halogen, (C1-C10) alkyl, (C1-C10) alkoxy, (C1-C3) arylalkyl, cycloalkyl or (C1-C3) alkoxy, each optionally substituted with halogen, (C1-) alkoxy C3), (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, cyano or nitro.

Description

2-aminoindole compounds and methods for the treatment of malaria

5 Background of the invention

Malaria is a vector-borne infectious disease caused by protozoan parasites and is widespread in tropical and subtropical regions, which include parts of the Americas, Asia and Africa. Of the five species of Plasmodium parasites that can infect humans (P. falciparum, P. vivax, P. ovale, P. 10 malariae and P. knowlesi), the most serious forms of the disease are caused by P. falciparum and P. vivax. Of the approximately 515 million people infected annually, between one and three million people, most of them are young children in sub-Saharan Africa, die of the disease. The current armament of approved antimalarial drugs, such as chloroquine, atovaquone, pyrimethamine and sulfadoxine, is limited to only a few targets within the human malaria parasite, and the increasing widespread resistance to drugs

15 current is motivating the development of new antimalarial agents that have new biological targets.

French patent application FR 2 921 061 discloses the use of indole derivatives and their pharmaceutically acceptable salts for the treatment of malaria. FR 2 921 061 also discloses pharmaceutical compositions comprising indolone derivatives.

Summary of the Invention

It has now been found that a novel class of compounds based on a 2-aminoindole scaffolding (referred to herein as "2-aminoindoles") is effective in treating malaria. Compounds

25 representatives disclosed herein have potent antimalarial activity in vitro and in vivo and probably act by a mechanism that has not been used in the development of malaria drugs. It has been shown that some class representatives cure malaria in a rodent model.

Accordingly, in one embodiment, the present invention relates to compounds for use in the treatment of a subject with malaria, administering to the subject an effective amount of a 2-aminoindole compound of the invention.

In another embodiment, the invention relates to 2-aminoindole compounds described herein.

In another embodiment, the invention relates to compositions (for example, pharmaceutical compositions) comprising a 2-aminoindole compound described herein.

In a further embodiment, the invention relates to methods of preparing 2-aminoindole compounds described herein.

40 Brief description of the drawings

FIG. 1 is a graph representing the in vivo efficacy of compound 1 after IP administration for four days at various doses in an animal (rodent) model of malaria. A dose-response relationship was observed. A dose of 50 mg / kg effectively treated malaria in the animal model.

45 FIGS. 2A and 2B are graphs that represent the in vivo efficacy of the enantiomers of compound 1 (ie, compounds 2 and 3). Although both compounds were effective in reducing parasitemia at a dose of 50 mg / kg, a dose of 50 mg / kg of compound 3 effectively treated malaria in the animal model.

50 FIGS. 3A-D are graphs that show efficacy data in vivo (parasitemia and recrudescence) in a mouse malaria model for compounds 155 (FIGS. 3A and 3B) and 142 (FIGS. 3C and 3D). FIG. 3D: On day 5, 0% of the control group was without parasites while 100 / mg / kg / day of treatment with compound 142 produced 20% without parasites and 200 / mg / kg / day of treatment with the Compound 142 produced 80% without parasites. On day 30, 60% of the group treated with 200 / mg / kg / day of compound 142 was without parasites.

Detailed description of the invention

In a first embodiment, the present invention is a compound for use in treating a subject with malaria, administering to the subject an effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, in which

R1, R2, R3 and R4 are independently hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C6) alkyl, alkenyl (C1-C6), alkynyl (C1- C6), alkoxy (C1-C6), aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1- C3), N (R7) 2, C (= NOH) NH2, NR7CON (R7) 2, CON (R7) 2, CO2R7, COR8, OC (O) R7, SO2N (R7) 2,

10 SO2R8, NR7COR8, NR7CO2R8, NR7SO2R8 and OC (= O) N (R7) 2, each optionally substituted with one or more groups represented by R6; wherein R2 and R3, together with the carbons to which they are attached, can form a heterocyclyl or heteroaryl, in which the heterocyclyl or heteroaryl formed is optionally substituted with one or more groups represented by R6;

R5 is aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl (C1-C3), arylheterocyclyl (C3-C10), arylalkoxy (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclyl-alkyl (C1-C3) C3), alkylheteroaryl, (C1-C6) alkyl, (C1-C4) alkoxy, each optionally substituted with one to three groups represented by R6; each R6 is independently selected from halogen (e.g., fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C4) alkyl, haloalkyl (C1-C3), hydroxyalkyl (C1-C4), alkoxy (C1 -C4), haloalkoxy (C1-C4), aryl,

20 haloaryl, cycloalkyl, aryl (C1-C3) alkyl, arylalkoxy (C1-C4), heterocyclyl, N (R7) 2, C (= NOH) NH2, NR7CON (R7) 2, CON (R7) 2, CO2R7, COR8, OC (O) R8, S, SO2N (R8) 2, SO2R8, SR8, S-(C1-C3) -cycloalkyl alkyl, NR 7COR8,

NR 7CO2R8, NR8SO2R8, S (= O) R8, -O-cycloalkyl, -O-heterocyclyl, adamantyl, OC (= O) N (R7) 2,

Y

each R7 is independently selected from hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C3) alkyl, each

One optionally substituted with halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, halo (C1-C3) haloalkoxy, cyano or nitro ; and each R8 is independently selected from hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C10) alkyl, (C1-C10) alkoxy, aryl, arylalkyl (C1-C3), cycloalkyl or arylalkoxy ( C1-C3), each optionally substituted with halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy, (C1-C3) alkyl,

Haloalkyl (C1-C3), haloalkoxy (C1-C3), cyano or nitro.

In a second embodiment, the present invention is a compound of formula IIa:

or a pharmaceutically acceptable salt thereof, in which

X is carbon or nitrogen; Y is carbon or nitrogen; R1a is hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, aryl (C1-C3) alkyl,

5 heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R5a) 2, C (= NOH) NH2, NR5aCON (R5a) 2, CON ( R5a) 2, CO2R5a, COR6a, OC (O) R5a, SO2N (R5a) 2, SO2R6a, NR5aCOR6a, NR5aCO2R6a, NR5aSO2R6a and OC (= O) N (R5a) 2, each optionally substituted with one or more groups represented by R4a; R2a is (C1-C6) alkyl, (C1-C6) alkoxy, S-C1-C6 alkyl, SO-C1-C6 alkyl or SO2-C1-C6 alkyl or

10 optionally substituted with one or more groups represented by R4a; R3a is halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C6) alkyl or (C1-C6) alkoxy, each optionally substituted with one or more groups represented by R4a; Each R4a is independently selected from halogen (e.g., fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C4) alkyl, haloalkyl (C1-C3), hydroxyalkyl (C1-C4), alkoxy (C1 -C4), haloalkoxy (C1-C4), aryl,

15 haloaryl, cycloalkyl, aryl (C1-C3) alkyl, arylalkoxy (C1-C4), heterocyclyl, N (R5a) 2, C (= NOH) NH2, NR5aCON (R5a) 2, CON (R5a) 2, CO2R5a, COR6a, OC (O) R5a, S, SO2N (R5a) 2, SO2R6a, SR6a, S-(C1-C3) -cycloalkyl alkyl, NR 5aCOR6a,

NR5CO2R6a, NR5aSO2R6a, S (= O) R6a, -O-cycloalkyl, -O-heterocyclyl, adamantyl, OC (= O) N (R5a) 2,

Y

each R5a is independently selected from hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C6) alkyl, each

One optionally substituted with halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, halo (C1-C3) haloalkoxy, cyano or nitro ; and each R6a is independently selected from hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C10) alkyl, (C1-C10) alkoxy, aryl (C1-C3) alkyl, cycloalkyl or aryl (C1-) alkoxy C3), each optionally substituted with halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy, (C1-C3) alkyl,

Haloalkyl (C1-C3), haloalkoxy (C1-C3), cyano or nitro.

In a third embodiment, the present invention is a pharmaceutical composition comprising the compound of formula IIa, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In a fourth embodiment, the present invention is a compound of formula VI:

or a pharmaceutically acceptable salt thereof, in which

R1b is hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6 alkoxy) ), aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R3b) 2 ,

40 C (= NOH) NH2, NR3CON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3b, SO2N (R3b) 2, SO2R4b, NR3COR4b, NR3aCO2R4b, NR3bSO2R4b and OC (= O) N (R3b) 2, each optionally substituted with one or more groups represented by R2b; each R2b is independently selected from halogen (for example, fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C4) alkyl, haloalkyl (C1-C3), hydroxyalkyl (C1-C4), alkoxy (C1 -C4), haloalkoxy (C1-C4), aryl,

45 haloaryl, cycloalkyl, aryl (C1-C3) alkyl, arylalkoxy (C1-C4), heterocyclyl, N (R3a) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3b, S, SO2N (R3b) 2, SO2R4b, SR4b, S-(C1-C3) -cycloalkyl alkyl, NR3bCOR4b, NR3bCO2R4b, NR3bSO2R4b, S (= O) R3b, -O-cycloalkyl, -O- heterocyclyl, adamantyl, OC (= O) N (R3b) 2,

each R3b is independently selected from hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C3) alkyl, each optionally substituted with halogen (e.g., fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy, alkyl (C1

C3), haloalkyl (C1-C3), haloalkoxy (C1-C3), cyano or nitro; and each R4b is independently selected from hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C10) alkyl, (C1-C10) alkoxy, aryl, arylalkyl (C1-C3), cycloalkyl or arylalkoxy ( C1-C3), each optionally substituted with halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, halo (C1-C3) haloalkoxy ), cyano or nitro.

10 Alternative values and values for the variables in structural formula I are provided in the following paragraphs:

R1 is hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-alkenyl)

C6), (C1-C6) alkynyl, (C1-C6) alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1 -C3), hydroxyalkyl (C1-C3), N (R7) 2, C (= NOH) NH2, NR7CON (R7) 2, CON (R7) 2, CO2R7, COR8, OC (O) R7, SO2N (R7) 2, SO2R8, NR7COR8, NR7CO2R8, NR7SO2R8 and OC (= O) N (R7) 2, each optionally substituted with one or more groups represented by R6. Alternatively, R1 is hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C4) alkyl or (C1-C4) alkoxy. Alternatively,

20 R1 is chlorine.

R2 is hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6 alkoxy) ), aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R7) 2 , C (= NOH) NH2,

25 NR7CON (R7) 2, CON (R7) 2, CO2R7, COR8, OC (O) R7, SO2N (R7) 2, SO2R8, NR7COR8, NR7CO2R8, NR7SO2R8 and OC (= O) N (R7) 2, each optionally substituted with one or more groups represented by R6. Alternatively, R2 is hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C4) alkyl or (C1-C4) alkoxy. Alternatively, R2 is ethoxy. Alternatively, R2 is methoxy. Alternatively, R2 is hydroxy.

R3 is hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-) alkoxy C6), aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R7) 2, C (= NOH) NH2, NR7CON (R7) 2, CON (R7) 2, CO2R7, COR8, OC (O) R7, SO2N (R7) 2, SO2R8, NR7COR8, NR7CO2R8, NR7SO2R8 and OC (= O) N (R7) 2, each optionally substituted with one or more groups represented by R6. Alternatively,

R3 is hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C4) alkyl or (C1-C4) alkoxy. Alternatively, R3 is chlorine. Alternatively, R3 is fluorine. Alternatively, R3 is methoxy.

Alternatively, R2 and R3, together with the carbons to which they are attached, form a heterocyclyl or heteroaryl, in which the heterocyclyl or heteroaryl formed is optionally substituted with one or more groups represented by R6.

R4 is hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-) alkoxy C6), aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R7) 2, C (= NOH) NH2, NR7CON (R7) 2, CON (R7) 2, CO2R7, COR8, OC (O) R7, SO2N (R7) 2, SO2R8, NR7COR8, NR7CO2R8, NR7SO2R8 and

OC (= O) N (R7) 2, each optionally substituted with one or more groups represented by R6. Alternatively, R4 is hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C4) alkyl or (C1-C4) alkoxy.

R5 is aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl (C1-C3), arylheterocyclyl (C3-C10), arylalkoxy (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclyl-C3-alkyl ), alkylheteroaryl, (C1-C6) alkyl, 50 (C1-C4) alkoxy, each optionally substituted with one to three groups represented by R6.

each R6 is independently selected from halogen (e.g., fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C4) alkyl, haloalkyl (C1-C3), hydroxyalkyl (C1-C4), alkoxy (C1 -C4), haloalkoxy (C1-C4), aryl, haloaryl, cycloalkyl, arylalkyl (C1-C3), arylalkoxy (C1-C4), heterocyclyl, N (R7) 2, C (= NOH) NH2, NR7CON (R7) 2, WITH (R7) 2,

55 CO2R7, COR8, OC (O) R8, S, SO2N (R8) 2, SO2R8, SR8, S-alkyl (C1-C3) -cycloalkyl, NR7COR8, NR7CO2R8, NR8SO2R8, S (= O) R8, -O- cycloalkyl, -O-heterocyclyl, adamantyl, OC (= O) N (R7) 2,

each R7 is independently selected from hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C3) alkyl, each optionally substituted with halogen (e.g., fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy, (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, cyano or nitro; Y

each R8 is independently selected from hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C10) alkyl, (C1-C10) alkoxy, aryl, arylalkyl (C1-C3), cycloalkyl or arylalkoxy (C1 -C3), each optionally substituted with halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl,

10 haloalkoxy (C1-C3), cyano or nitro.

In another embodiment, the present invention is a compound for use in treating a subject with malaria, administering to the subject an effective amount of a compound of formula II:

or a pharmaceutically acceptable salt thereof, in which alternative values and values for R1, R2 and R3 are as defined above for structural formula I, X is carbon or nitrogen and Y is carbon or nitrogen. Alternatively, X is carbon and Y is carbon. Alternatively, X is nitrogen and Y is carbon.

In another embodiment, the present invention is a compound for use in treating a subject with malaria, administering to the subject in need thereof an effective amount of a compound of formula III:

or a pharmaceutically acceptable salt thereof, in which alternative values and values for R1, R2 and R3 are as defined above for structural formula I.

In another embodiment, the present invention is a compound for use in treating a subject with malaria, administering to the subject an effective amount of a compound of formula (XXIII)

or a pharmaceutically acceptable salt thereof, in which alternative values and values for R1, R2 and R3 are as defined above for structural formula I.

In another embodiment, the present invention is a compound for use in treating a subject with malaria, administering to the subject in need thereof an effective amount of a compound of formula IV:

or a pharmaceutically acceptable salt thereof, in which alternative values and values for R1 and R2 are as defined above for structural formula I.

In another embodiment, the present invention is a compound for use in treating a subject with malaria, administering to the subject an effective amount of a compound of formula V:

or a pharmaceutically acceptable salt thereof, in which alternative values and values for R1 are as they have been

20 defined above for structural formula I.

Alternative values and values for the variables in structural formula IIa are provided in the following

Paragraphs: 25 X is carbon or nitrogen. Alternatively, X is carbon.

And it is carbon or nitrogen. Alternatively, Y is carbon.

R1a is hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C6) alkyl, alkenyl

30 (C1-C6), (C1-C6) alkynyl, (C1-C6) alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, aryl (C1-C3) alkyl,

heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R5a) 2, C (= NOH) NH2, NR5aCON (R5a) 2, CON (R5a ) 2, CO2R5a, COR6a, OC (O) R5a, SO2N (R5a) 2, SO2R6a, NR5aCOR6a, NR5aCO2R6a, NR5aSO2R6a and OC (= O) N (R5a) 2, each optionally substituted with one or more groups represented by R4a . Alternatively, R1a is halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C4) alkyl or

5 (C1-C4) alkoxy. Alternatively, R1a is chlorine.

R2a is (C1-C6) alkyl, (C1-C6) alkoxy, S-C1-C6 alkyl, SO-C1-C6 alkyl, SO2-C1-C6 alkyl, optionally substituted with one or more groups represented by R4a. Alternatively, R2a is (C1-C6) alkoxy. Alternatively, R2a is ethoxy.

R3a is halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C6) alkyl or (C1-C6) alkoxy, each optionally substituted with one or more groups represented by R4a. Alternatively R3a is halogen. Alternatively, R3a is fluorine.

Each R4a is independently selected from halogen (for example, fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C4) alkyl, haloalkyl (C1-C3), hydroxyalkyl (C1-C4), alkoxy ( C1-C4), haloalkoxy (C1-C4), aryl, haloaryl, cycloalkyl, arylalkyl (C1-C3), arylalkoxy (C1-C4), heterocyclyl, N (R5a) 2, C (= NOH) NH2, NR5aCON (R5a ) 2, CON (R5a) 2, CO2R5a, COR6a, OC (O) R5a, S, SO2N (R5a) 2, SO2R6a, SR6a, S-alkyl (C1-C3) -cycloalkyl, NR5aCOR6a, NR5CO2R6a,

NR5aSO2R6a, S (= O) R6a, -O-cycloalkyl, -O-heterocyclyl, adamantyl, OC (= O) N (R5a) 2, 20 (C1-C3) alkyl -C (= O) NH-alkyl (C1 -C3) -O-(C1-C3) alkyl -O-(C1-C3) -NHR7a alkyl.

Each R5a is independently selected from hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C6) alkyl, each optionally substituted with halogen (e.g., fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, halo (C1-C3) haloalkoxy, cyano or nitro.

Each R6a is independently selected from hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C10) alkyl, (C1-C10) alkoxy, aryl (C1-C3) alkyl, cycloalkyl or aryl (C1-) alkoxy C3), each optionally substituted with halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, halo (C1-C3) haloalkoxy, cyano or nitro.

In another embodiment, the present invention is a compound of formula IIIa:

35 or a pharmaceutically acceptable salt thereof, in which alternative values and values for R1a, R2a and R3a and are as defined above for formula IIa.

In another embodiment, the present invention is a compound of formula XXIIIa:

or a pharmaceutically acceptable salt thereof, in which alternative values and values for R1a, R2a and R3a and are as defined above for formula IIa.

In another embodiment, R1, R2, R3 and R4 are independently hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C4) alkyl or (C1-C4) alkoxy and the rest of the variables are as have been defined above for the formula

I.

In another embodiment, R3 is chlorine and the rest of the variables are as defined above for formula I.

In another embodiment, R1 is chlorine, R2 is ethoxy, R3 is fluorine, X is carbon, Y is carbon and the rest of the variables are as defined above for formula II.

In another embodiment, R1 is chlorine, R2 and R3 are methoxy, X is nitrogen, Y is carbon and the other variables are as defined above for formula II.

In another embodiment, R1 is chlorine, R2 is hydroxyl, R3 is fluorine and the remaining variables are as defined above for formula II.

In another embodiment, R1 is chlorine, R2 is hydroxyl, R3 is fluorine, X is carbon, Y is carbon and the rest of the variables are as defined above for formula II.

In another embodiment, R1 is chlorine, R2 ethoxy and R3 is fluorine and the rest of the variables are as defined above for formula III.

In another embodiment, R1 is chlorine and the rest of the variables are as defined above for formula V.

In another embodiment, R1a is halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C4) alkyl or (C1-C4) alkoxy and the rest of variables are as defined above for formula IIa.

In another embodiment, R1a is (C1-C4) alkoxy and the remaining variables are as defined above for formula IIa.

In another embodiment, R1a is halogen and the rest of the variables are as defined above for formula IIa.

In another embodiment, R1a is chlorine, R2a and R3a are methoxy, X is nitrogen, Y is carbon and the rest of the variables are as defined above for formula IIa.

In another embodiment, R1b is halogen, (C1-C6) alkyl or (C1-C6) alkoxy and the remaining variables are as defined above for formula VI.

In another embodiment, R1b is halogen and the rest of the variables are as defined above for formula 45 VI.

In another embodiment, R1b is chlorine and the rest of the variables are as defined above for formula VI.

In another embodiment, R1b is methyl and the rest of the variables are as defined above for formula VI. In another embodiment, R1b is methoxy and the rest of the variables are as defined above for formula VI.

Specific examples of the compounds of the invention, and their respective IC50 values, are presented in the Table

1. The compounds disclosed in Table 1 are encompassed by the scope of the invention.

Table 1: Compounds encompassed by the invention with the indicated IC50 values (see table legend)

* represents IC50 of less than 15 Ma 5 M; ** represents IC50 of less than 5 Ma 1 M; *** represents IC50 of less than 1 M at 500 nM; **** represents IC50 of less than 500 nM to 100 nM; ***** represents IC50 of less than 100 nM to 1 nM. The indicated IC50 values were determined with respect to reductions in parasitemia

5 observed for strain 3D7 of P. falciparum.

Table 1a: Compounds disclosed herein, but not encompassed by the invention, with indicated IC50 values (see table legend)

* represents IC50 of less than 15 Ma 5 M; ** represents IC50 of less than 5 Ma 1 M; *** represents IC50 of less than 1 M at 500 nM; **** represents IC50 of less than 500 nM to 100 nM; ***** represents IC50 of less than 100 nM to 1 nM. The indicated IC50 values were determined with respect to reductions in parasitemia

observed for strain 3D7 of P. falciparum.

The compounds of the invention may be present in the form of pharmaceutically acceptable salts. For use in medicines, the salts of the compounds of the invention refer to non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salt forms include pharmaceutically acceptable acid / anionic or basic / cationic salts.

Pharmaceutically acceptable acid / anionic salts include the salts acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dichlorohydrate, edetate, edisilate, stolate, silate, fumarate, gluceptate, gluconate, glutamate , glycolylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, napsilate, nitrate, pamoate, pantothenate, phosphate, stearate, phosphate, stearate, phosphate , subacetate, succinate, sulfate, hydrogen sulfate, tannate, tartrate, teoclate, tosylate and triiodide.

The pharmaceutically acceptable basic / cationic salts include the sodium, potassium, calcium, magnesium, diethanolamine, N-methyl-D-glucamine, L-lysine, L-arginine, ammonium, ethanolamine, piperazine and triethanolamine salts.

The disclosed compounds can be used alone (ie, as monotherapy) or in combination with another therapeutic agent effective to treat malaria.

Alternatively, a pharmaceutical composition of the invention may comprise an antimalarial compound disclosed herein or a pharmaceutical salt thereof, as the sole pharmaceutically active agent in the pharmaceutical composition. The disclosed antimalarial compounds can be used alone or in a combination therapy with one or more additional agents for the treatment of malaria.

A pharmaceutical composition of the invention may comprise, alternatively or in addition to an antimalarial compound disclosed herein, a pharmaceutically acceptable salt of an antimalarial compound disclosed herein or a pharmaceutically active prodrug or metabolite of a compound or salt such and one or more pharmaceutically acceptable vehicles for it. Alternatively, a pharmaceutical composition of the invention may comprise an antimalarial compound disclosed herein or a pharmaceutical salt thereof as the sole pharmaceutically active agent in the pharmaceutical composition.

The invention includes the use of compounds in the treatment of malaria in a subject in need thereof.

Administering to the subject an effective amount of an antimalarial compound disclosed herein or a pharmaceutically acceptable salt thereof or a composition thereof (for example, a pharmaceutical composition comprising an antimalarial compound and a pharmaceutically acceptable carrier). The compounds disclosed herein can be used in the treatment of malaria. Thus, in one embodiment, the invention relates to the use of a compound disclosed herein for the treatment of malaria in a subject in need thereof. In other embodiments, the invention relates to the use of a compound disclosed herein in the treatment of malaria and the use of a compound disclosed herein in the manufacture of a medicament for the treatment of malaria. As used herein, "treating" or "treatment" includes both therapeutic and prophylactic treatment. Therapeutic treatment includes reducing the symptoms associated with a disease or condition and / or increasing the longevity of a

45 subject with the disease or condition. Prophylactic treatment includes delaying the onset of a disease or condition in a subject at risk of developing the disease or condition or reducing the probability that a subject will then develop the disease or condition in a subject that is at risk of developing the disease or condition .

As used herein, an "effective amount" is an amount sufficient to achieve a desired effect under the conditions of administration, in vitro, in vivo or ex vivo, such as, for example, an amount sufficient to treat malaria in a subject. The efficacy of a compound can be determined by suitable methods known to those skilled in the art that include those described herein.

As defined herein, a "therapeutically effective amount" is an amount sufficient to achieve a desired therapeutic or prophylactic effect on a subject in need thereof under the conditions of administration, such as, for example, an amount sufficient for Treat malaria in a subject. The effectiveness of a therapy can be determined by suitable methods known to those skilled in the art.

An embodiment of the invention includes administering an antimalarial compound disclosed herein,

or composition thereof, in a combination therapy with one or more additional agents for the treatment of malaria. Agents for the treatment of malaria include quinine, atovaquone, chloroquine, cycloguanyl, hydroxychloroquine, amodiaquine, pyrimethamine, sulfadoxine, proguanyl, mefloquine, halofantrine, pamaquina, primaquine, artemesinin, artemether, artesunate, artenimol, lumefantrine, dihydroamisin, dihydroamisin, dihydroamisin, dihydroamisin, dihydroamisin

65 doxycycline and clindamycin.

The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally or intraperitoneally. Additionally, the compounds of the present invention can

5 administered intranasally or transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise, as an active ingredient, both compounds and a corresponding pharmaceutically acceptable salt of a compound of the present invention.

To prepare the pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be both solid and liquid. Solid form preparations include powders, tablets, pills, capsules, seals, suppositories and dispersible granules. A solid carrier can be one or more substances that can also act as diluents, flavorings, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or an encapsulation material. In powders, the vehicle is a finely divided solid that is in a mixture with the finely active ingredient

15 divided.

In tablets, the active ingredient is mixed with the vehicle that has the necessary bonding properties in suitable proportions and is compacted in the desired shape and size.

The powders and tablets preferably contain from about one to about seventy percent of the active substance. Suitable vehicles are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. Tablets, powders, seals, lozenges, fast melting strips, capsules and pills can be used as solid dosage forms containing the principle

25 active suitable for oral administration.

Suppositories consisting of a combination of the active substance and a suppository base are also suitable for enteral administration. Suitable as suppository bases are, for example, natural or synthetic triglycerides, paraffins, polyethylene glycols or higher alkanols. It is also possible to use rectal gelatin capsules containing a combination of the active substance and a base material; Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons. To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, melts first and the active ingredient disperses homogeneously inside, as if stirring. The homogeneous molten mixture is then poured into molds of convenient size, allowed to cool, and thus solidify.

Preparations in liquid form include solutions, suspensions, retention enemas and emulsions, for example, water or solutions of propylene glycol in water. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavors, stabilizers and thickeners as desired. Aqueous suspensions may be prepared for oral administration by dispersing the finely divided active ingredient in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents.

The pharmaceutical composition is preferably in unit dosage form. In such form, the composition is subdivided into unit doses containing appropriate amounts of the active substance. The unit dosage form may be a packaged preparation, the package containing discrete amounts of, for example, tablets, powders and capsules in vials or ampoules. The unit dosage form may also be a tablet, seal, capsule or lozenge, or it may be the appropriate amount of any of these in packaged form.

Dosages can be varied depending on the requirements of the patient, the severity of the condition being treated and the compound that is used. Determination of the appropriate dosage for a situation

55 particular is within the experience in the field. The pharmaceutical composition may also contain, if desired, other compatible therapeutic agents.

SYNTHETIC METHODS

As described herein, it has been found that the 2-aminoindole compounds of the invention can be produced by aminating a 2-oxindole compound with tert-butyldimethylsilylamine (TBDMSNH2), for example, in the presence of SnCl4 and an agent selected from triethylamine, N-ethyldiisopropylamine or N-methylmorpholine (NMM). It has also been found that aminating 2-oxindole compounds with TBDMSNH2 preserves stereospecificity. Thus, in another embodiment, the invention relates to amination methods of a 265 oxindole compound to produce a 2-aminoindole compound using tert-butyldimethylsilylamine (TBDMSNH2) in the presence of SnCl4 and a triethylamine selected agent, N-ethyldiisopropylamine or N-methylmorpholine (NMM). Schemes

Representative for such a method are described herein in Examples 8-10, Schemes 20-22.

In a particular embodiment, TBDMSNH2 is used in an enantioselective method of preparing a 2-aminoindole. A representative scheme for such a method is described herein in Example 10, Scheme

5 22.

In one embodiment, the invention relates to a method of preparing a compound represented by the formula

VII:

or a pharmaceutically acceptable salt thereof, in which

Each R1b is independently selected from hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R3b) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3, SO2N (R3b) 2, SO2R4b, NR3COR4, NR3bCO2R4b, NR3bSO2R4b and OC (= O) N (R3b) 2, each optionally

20 substituted with one or more groups represented by R2b; each R2b is independently selected from halogen (for example, fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C4) alkyl, haloalkyl (C1-C3), hydroxyalkyl (C1-C4), alkoxy (C1 -C4), haloalkoxy (C1-C4), aryl, haloaryl, cycloalkyl, arylalkyl (C1-C3), arylalkoxy (C1-C4), heterocyclyl, N (R3b) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3b, S, SO2N (R3b) 2, SO2R4b, SR4b, S-(C1-C3) -cycloalkyl alkyl, NR 3bCOR4b,

NR3bCO2R4b, NR3bSO2R4b, S (= O) R3b, -O-cycloalkyl, -O-heterocyclyl, adamantyl, OC (= O) N (R3) 2, and

each R3b is independently selected from hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C3) alkyl, each optionally substituted with halogen (e.g., fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, halo (C1-C3) alkoxy, cyano or nitro; Y

Each R4b is independently selected from hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C10) alkyl, (C1-C10) alkoxy, aryl, arylalkyl (C1-C3), cycloalkyl or arylalkoxy ( C1-C3), each optionally substituted with halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, halo (C1-C3) haloalkoxy ), cyano or nitro; and R5b is hydrogen or C (= O) O (C1-C3) alkyl,

35 comprising the method:

aminating a compound represented by formula X:

with tert-butyldimethylsilylamine (TBDMSNH2) in the presence of SnCl4 and an agent selected from the group comprising triethylamine, N-ethyldiisopropylamine or N-methylmorpholine (NMM), thus forming compound 5 represented by formula VII.

A representative scheme for such a method is described herein in Example 8, Scheme 20.

In a further embodiment, the invention relates to a method of preparing a compound represented by formula XVII:

in which the method comprises: aminating a compound represented by formula XXI:

20 with tert-butyldimethylsilylamine (TBDMSNH2) in the presence of SnCl4 and an agent selected from triethylamine, Netildiisopropylamine or N-methylmorpholine (NMM), thus forming the compound represented by formula XVII.

In a particular embodiment, the amination step in the synthetic methods described herein is carried out at a temperature of about 120 ° C (for example, in a microwave) for about 25 to about 60 minutes in the presence of tetrahydrofuran (THF) .

As an alternative to the enantioselective amination step described herein, chiral separation techniques and / or methods can be employed to prepare enantiomers of 2-aminoindole compounds. Suitable chiral separation techniques and methods include, for example, various techniques and methods of

30 well-known chromatography separation. An appropriate technique and / or method of separating enantiomers from a racemic mixture of a 2-aminoindole compound disclosed herein can be readily determined by those skilled in the art.

A representative scheme for such a method is described herein in Example 10, Scheme 35 22.

In addition to the methods described above, supercritical fluid chromatography techniques and / or methods can be employed to prepare enantiomers of 2-aminoindole compounds, as described in the Example

18.

In another embodiment, the present invention is a method of preparing a compound represented by formula VII:

10 or a pharmaceutically acceptable salt thereof, in which

each R1b is independently selected from hydrogen, halogen (e.g., fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C6) alkyl, alkenyl (C1-C6), alkynyl (C1-C6), alkoxy (C1-C6), aryl, heteroaryl,

15 cycloalkyl, heterocyclyl, aryl (C1-C3) alkyl, heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R3b) 2, C (= NOH ) NH2, NR3CON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3b, SO2N (R3b) 2, SO2R4b, NR3COR4b, NR3CO2R4b, NR3SO2R4b and OC (= O) N (R3) 2, each optionally substituted with one or more groups represented by R2b; each R2b is independently selected from halogen (for example, fluorine, chlorine, bromine, iodine), nitro,

Cyan, hydroxy, (C1-C4) alkyl, halo (C1-C3) alkyl, hydroxyalkyl (C1-C4), alkoxy (C1-C4), haloalkoxy (C1-C4), aryl, haloaryl, cycloalkyl, arylalkyl (C1- C3), arylalkoxy (C1-C4), heterocyclyl, N (R3b) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3b, S, SO2N (R3b) 2, SO2R4b, SR4b, S-(C1-C3) alkylcycloalkyl, NR3bCOR4b,

-O-cycloalkyl, -O-heterocyclyl, adamantyl, OC (= O) N (R3b) 2,

Each R3b is independently selected from hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C3) alkyl, each optionally substituted with halogen (eg, fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy , (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, cyano or nitro; and each R4b is independently selected from hydrogen, halogen (for example, fluorine, chlorine, bromine,

Iodine), (C1-C10) alkyl, (C1-C10) alkoxy, aryl, aryl (C1-C3) alkyl, cycloalkyl or arylalkoxy (C1-C3), each optionally substituted with halogen (eg, fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, halo (C1-C3) haloalkoxy, cyano or nitro, comprising:

a) reacting a compound represented by formula VIII: 35

with an agent represented by formula IX:

where M is MgBr, Li or B (OH) 2, thus forming a compound represented by the formula X:

Y

b) aminating the compound of formula X with tert-butyldimethylsilylamine (TBDMSNH2) in the presence of SnCl4 and an agent selected from triethylamine, N-ethyldiisopropylamine or N-methylmorpholine (NMM), thus forming the

compound represented by formula VII.

A representative scheme for such a method is described herein in Example 8, Scheme 20.

In another embodiment, the present invention is a method of preparing a compound represented by formula XI:

20 or a pharmaceutically acceptable salt thereof, in which

each R1b is independently selected from hydrogen, halogen (e.g., fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C6) alkyl, alkenyl (C1-C6), alkynyl (C1-C6), alkoxy (C1-C6), aryl, heteroaryl,

Cycloalkyl, heterocyclyl, arylalkyl (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R3b) 2, C (= NOH ) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3b, SO2N (R3b) 2, SO2R4b, NR3bCOR4b, NR3CO2R4b, NR3SO2R4b and OC (= O) N (R3b) 2, each optionally substituted with one or more groups represented by R2b; each R2b is independently selected from halogen (for example, fluorine, chlorine, bromine, iodine), nitro,

Cyano, hydroxy, (C1-C4) alkyl, halo (C1-C3) alkyl, hydroxy (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, aryl,

haloaryl, cycloalkyl, aryl (C1-C3) alkyl, arylalkoxy (C1-C4), heterocyclyl, N (R3b) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3b, S, SO2N (R3b) 2, SO2R4b, SR4b, S-(C1-C3) -cycloalkyl alkyl, NR3bCOR4b, NR3bCO2R4b, NR3bSO2R4b, S (= O) R3b, -O-cycloalkyl, -O-heterocyclyl , adamantyl, OC (= O) N (R3b) 2,

Each R3b is independently selected from hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C3) alkyl, each optionally substituted with halogen (eg, fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy , (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, cyano or nitro; and each R4b is independently selected from hydrogen, halogen (for example, fluorine, chlorine, bromine,

10 iodine), (C1-C10) alkyl, (C1-C10) alkoxy, aryl, aryl (C1-C3) alkyl, cycloalkyl or arylalkoxy (C1-C3), each optionally substituted with halogen (e.g., fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, halo (C1-C3) haloalkoxy, cyano or nitro, comprising:

a) reacting a compound represented by formula XII: 15

with an agent represented by formula XIII:

thus forming a compound represented by the formula XIV:

Y b) reacting the compound of formula XIV with H2 in the presence of Pd / C and, optionally, Ph2S, thus forming the compound represented by formula XV:

and c) oxidizing the compound of formula XV with potassium peroximonosulfate (OXONE), thus forming the compound represented by formula XVI:

Y

10 d) aminating the compound of formula XVI with tert-butyldimethylsilylamine (TBDMSNH2) in the presence of SnCl4 and an agent selected from triethylamine, N-ethyldiisopropylamine or N-methylmorpholine (NMM), thus forming the compound represented by formula XI.

A representative scheme for such a method is described herein in Example 9, Scheme 21.

In another embodiment, the present invention is a method of preparing a compound represented by formula XVII:

or a pharmaceutically acceptable salt thereof, in which

each R1b is independently selected from hydrogen, halogen (for example, fluorine, chlorine, bromine,

Iodine), nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, aryl (C1-) alkyl C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R3b) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3, SO2N (R3b) 2, SO2R4b, NR3COR4, NR3bCO2R4b, NR3bSO2R4b and OC (= O) N (R3b) 2, each optionally substituted with one or more groups represented by R2b;

Each R2b is independently selected from halogen (for example, fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C4) alkyl, haloalkyl (C1-C3), hydroxyalkyl (C1-C4), alkoxy ( C1-C4), haloalkoxy (C1-C4), aryl,

haloaryl, cycloalkyl, aryl (C1-C3) alkyl, arylalkoxy (C1-C4), heterocyclyl, N (R3b) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3b, S, SO2N (R3b) 2, SO2R4b, SR4b, S-(C1-C3) -cycloalkyl alkyl, NR3bCOR4b, NR3bCO2R4b, NR3bSO2R4b, S (= O) R3b, -O-cycloalkyl, -O-heterocyclyl , adamantyl, OC (= O) N (R3) 2,

Each R3b is independently selected from hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C3) alkyl, each optionally substituted with halogen (eg, fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy , (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, cyano or nitro; and each R4b is independently selected from hydrogen, halogen (for example, fluorine, chlorine, bromine,

10 iodine), (C1-C10) alkyl, (C1-C10) alkoxy, aryl, aryl (C1-C3) alkyl, cycloalkyl or arylalkoxy (C1-C3), each optionally substituted with halogen (e.g., fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, halo (C1-C3) haloalkoxy, cyano or nitro, comprising:

a) reduce a compound represented by formula XVIII:

with triethylsilane (Et3SiH) and trifluoroacetic acid (TFA), thus forming a compound represented by formula XIX:

Y b) oxidize the compound of formula XIX with an agent represented by formula XX:

in the presence of potassium hexamethyldisilazane (KHMDS) and tetrahydrofuran (THF), thus forming the compound represented by the formula XXI:

and c) aminating the compound of formula XXI with tert-butyldimethylsilylamine (TBDMSNH2) in the presence of SnCl4 and

5 an agent selected from the group comprising triethylamine, N-ethyldiisopropylamine and an agent selected from the group comprising triethylamine, N-ethyldiisopropylamine and N-methylmorpholine (NMM), thus forming the compound represented by the formula (XVII).

A representative scheme for such a method is described herein in Example 10, Scheme 10 22.

Alternative values and values for the variables in structural formula VI-XXI are provided in the following paragraphs:

R1b is hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine), nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-) alkoxy C6), aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R3b) 2, C (= NOH) NH2, NR3CON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3b, SO2N (R3b) 2, SO2R4b, NR3COR4b, NR3bCO2R4b, NR3bSO2R4b and OC (= O) N (R3b) 2, each optionally substituted with one or more groups represented by R2b.

Alternatively, R1b is halogen (for example, fluorine, chlorine, bromine, iodine), (C1-C6) alkyl or (C1-C6) alkoxy. Alternatively, R1b is halogen. Alternatively, R1b is chlorine. Alternatively, R1b is methyl. Alternatively, R1b is methoxy.

Each R2b is independently selected from halogen (for example, fluorine, chlorine, bromine, iodine), nitro, cyano,

Hydroxy, (C1-C4) alkyl, halo (C1-C3) alkyl, hydroxyalkyl (C1-C4), alkoxy (C1-C4), haloalkoxy (C1-C4), aryl, haloaryl, cycloalkyl, arylalkyl (C1-C3) , arylalkoxy (C1-C4), heterocyclyl, N (R3b) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2,

Each R3b is independently selected from hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C3) alkyl, each optionally substituted with halogen (e.g., fluorine, chlorine, bromine, iodine), (C1-C3) alkoxy , (C1-C3) alkyl, (C1-C3) haloalkyl, (C1-C3) haloalkoxy, cyano or nitro; Y

each R4b is independently selected from hydrogen, halogen (for example, fluorine, chlorine, bromine, iodine),

(C1-C10) alkyl, (C1-C10) alkoxy, aryl, aryl (C1-C3) alkyl, cycloalkyl or arylalkoxy (C1-C3), each optionally substituted with halogen (eg, fluorine, chlorine, bromine, iodine ), (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, halo (C1-C3) haloalkoxy, cyano or nitro.

DEFINITIONS

The term "alkyl", used alone or as part of a larger moiety such as "arylalkyl" or "haloalkyl", means a linear or branched hydrocarbon radical having 1-10 carbon atoms and includes, for example, methyl, ethyl, npropyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, i-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, ndecyl and the like.

An "alkenyl group" is an alkyl group in which at least one pair of adjacent methylenes are substituted with -CH = CH-.

An "alkynyl group" is an alkyl group in which at least one pair of adjacent methylenes are substituted with 50 C≡C-.

The term "cycloalkyl", used alone or as part of a larger moiety, means a monocyclic, bicyclic or tricyclic saturated hydrocarbon ring having 3-10 carbon atoms and includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, bicyclo [2.2.2] octyl, bicyclo [2.2.1] heptyl, spiro [4.4] nonane,

55 adamantyl and the like. Unless otherwise described, exemplary substituents for a group

substituted cycloalkyl include groups represented by R6.

"Aryl", used alone or as part of a larger moiety as in "arylalkyl," "arylalkoxy" or "aryloxyalkyl," means a 6-14 membered carbocyclic aromatic monocyclic or polycyclic ring system. Examples include phenyl,

Naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like. The term "aryl" also includes phenyl rings fused with a non-aromatic carbocyclic ring, a heterocyclyl group or with a heteroaryl group, in which the connection with an indole ring of the structural formula (I) is via the phenyl ring of the condensed ring system and includes, for example, dibenzo [b, d] furyl, quinoline or the like. The term "aryl" can be used interchangeably with the terms "aromatic group", "aryl ring", "aromatic ring", "aryl group" and "aromatic group". Unless otherwise described, exemplary substituents for a substituted aryl group include groups represented by R6.

"Hetero" refers to the replacement of at least one carbon atom member in a ring system with at least one heteroatom selected from N, S and O. A hetero ring may have 1, 2, 3 or 4 atom members of

15 carbon substituted with heteroatom.

"Heteroaryl", used alone or as part of a larger moiety such as "heteroarylalkyl" or "heteroarylalkoxy", means a 5-10 membered monovalent monocyclic and polycyclic heterocyclic ring radical containing 1 to 4 heteroatoms independently selected from N, O and S. The term "heteroaryl" also includes condensed monocyclic heteroaryl ring with a non-aromatic carbocyclic ring, with a heterocyclyl group or with an aryl ring, in which the connection with an indole ring of structural formula (I) is by the monocyclic heteroaryl ring of the condensed ring system. Heteroaryl groups include, but are not limited to, furyl, thienyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridinyl-N-oxide, pyridazinyl, pyriminyl, pyrimidyl, pyrimidyl indolizinyl, indolyl, isoindolyl, imidazo [4,5-b] pyridine,

25 benzo [b] furyl, benzo [b] thienyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, benzodioxolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzoxazolyl , benzothiazolyl, cinolinyl, phthalzinyl, quinazolinyl, quinoxalinyl, 1,8naphthyridinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-oxadiazolyl, 1,2,5-thiadiazolyl, 1,2 , 5-thiadiazolyl-1-oxide, 1,2,5-thiadiazolyl-1,1-dioxide, 1,3,4-thiadiazolyl, 1,2,4-triazinyl, 1,3,5-triazinyl, tetrazolyl and pteridinyl. The terms "heteroaryl", "heteroaromatic", "heteroaryl ring", "heteroaryl group" and "heteroaromatic group" are used interchangeably herein. "Heteroarylalkyl" means alkyl substituted with heteroaryl; and "heteroarylalkoxy" means alkoxy substituted with heteroaryl. Unless otherwise described, exemplary substituents for a substituted heteroaryl group include the groups represented by R6.

The term "heterocyclyl" means a saturated, or partially unsaturated, 4, 5, 6 and 7-membered heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O and S. Exemplary heterocyclyls include azetidine, pyrrolidine, pyrrolidine- 2-one, 1-methylpyrrolidin-2-one, piperidine, piperidin-2-one, 2-pyridone, 4pyridone, piperazine, 1- (2,2,2-trifluoroethyl) piperazine, piperazin-2-one, 5,6 -dihydropyrimidin-4-one, pyrimidin-4-one, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, tetrahydrothiopyran, isoxazolidine, 1,3-dioxolane, 1,3-dithiolane, 1,3-dioxane, 1,4-dioxane, 1,3 -dithiano, 1,4-dithiano, oxazolidin-2-one, imidazolidin-2-one, imidazolidin-2,4-dione, tetrahydropyrimidin-2 (1H) -one, morpholine, N-methylmorpholine, morpholin-3-one, 1,3-oxazinan-2-one, thiomorpholine, 1,1 thiomorpholine dioxide, 1,1-tetrahydro-1,2,5-thiaoxazole dioxide, 1,1-tetrahydro-2H-1,2-thiazine dioxide, 1,1-hexahydro-1,2,6-thiadiazine dioxide, 1,1-dioxide tetrahydro-1,2,5-thiadiazole and 1,1-isothiazolidine dioxide. Unless otherwise described, exemplary substituents for a substituted heterocyclyl group include groups

45 represented by R6.

The term "alkoxy" means an alkyl radical linked by an oxygen bonding atom. "C1-C4 alkoxy" includes methoxy, ethoxy, propoxy and butoxy.

The term "cycloalkoxy" means a cycloalkyl radical linked by an oxygen bonding atom. "Cycloalkoxy (C3-C6)" includes cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.

The term "aryloxy" means an aryl moiety linked by an oxygen bonding atom. Aryloxy includes, but is not limited to, phenoxy.

55 The terms "halogen" and "halo" are used interchangeably herein and each refers to fluorine, chlorine, bromine or iodine.

As used herein, the terms "subject" and "patient" may be used interchangeably, and means a mammal in need of treatment, for example, pets (eg, dogs, cats and the like), farm animals (for example, cows, pigs, horses, sheep, goats and the like) and laboratory animals (for example, rats, mice, guinea pigs and the like). Normally, the subject is a human being in need of treatment.

65 Malaria is a parasitic infection of red blood cells produced by eukaryotic protists of the genus Plasmodium on the Apicomplexa edge. Human malaria is known to be produced by five species of

Different Plasmodium: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae or Plasmodium knowlesi. Malaria parasites are transmitted by female Anopheles mosquitoes. The parasites multiply within the red blood cells, causing symptoms that include symptoms of anemia (mild dizziness, dyspnea, tachycardia), in addition to other general symptoms such as an enlarged spleen, fatigue, fever, chills, 5 nausea, disease similar to flu and, in severe cases, coma and death. The compounds described herein are useful in the treatment of human malaria produced by a species of Plasmodium, such as Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae or Plasmodium knowlesi. In a particular embodiment, the invention relates to a compound for use in the treatment of a malaria produced by Plasmodium falciparum. Both drug resistant and drug sensitive strains of

10 Plasmodium are intended to be included in this document.

Certain of the disclosed compounds may exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. The enantiomers are pairs of stereoisomers whose mirror images are not superimposable, most commonly because they contain an asymmetrically substituted carbon atom that acts as a chiral center. "Enantiomer" means one of a pair of molecules that are mirror images of each other and are not superimposable. Diastereomers are stereoisomers that are not related as mirror images, most commonly because they contain two or more asymmetrically substituted carbon atoms. The symbol "*" in a structural formula represents the presence of a chiral carbon center. "R" and "S" represent the configuration of substituents 20 around one or more chiral carbon atoms. Thus, "R *" and "S *" indicate the relative configurations of substituents around one or more chiral carbon atoms. The enantiomers of a compound can be prepared, for example, by separating an enantiomer from a racemate using one or more well-known techniques and methods, such as, for example, chiral chromatography and separation methods based on it. The appropriate technique and / or method for separating an enantiomer from a compound described herein from a mixture

Racemic can easily be determined by those skilled in the art.

"Racemate" or "racemic mixture" means a compound containing two enantiomers, in which such mixtures have no optical activity; that is, they do not rotate the plane of polarized light.

"Geometric isomer" means isomers that differ in the orientation of substituent atoms in relation to a carbon-carbon double bond, with a cycloalkyl ring, or with a bicyclic system linked by bridges. Atoms (other than H) on each side of a carbon-carbon double bond can be in an E configuration (the substituents are on opposite sides of the carbon-carbon double bond) or Z (the substituents are oriented on the same side).

"R", "S", "S *", "R *", "E", "Z", "cis" and "trans" indicate configurations with respect to the core molecule.

Certain of the disclosed compounds may exist in various tautomeric forms. Tautomeric forms exist when a compound is a mixture of two or more structurally distinct compounds that are in rapid

40 balance Certain compounds of the invention exist as tautomeric forms. For example, the following compound represented by structural formula (A) and (B) includes at least the following tautomeric forms:

It should be understood that when a tautomeric form of a compound is represented by name or structure, all tautomeric forms of the compound are included.

50 Certain of the disclosed compounds may exist in atropisomeric forms. Atropisomers are stereoisomers resulting from impeded rotation around single bonds in which the steric deformation barrier to rotation is high enough to allow isolation of the conformers.

The compounds of the invention can be prepared as individual isomers therefore specific synthesis of

55 isomers how to resolve from an isomeric mixture. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by

fractional crystallization and free base regeneration), forming the acid salt form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and free acid regeneration), forming an ester or amide of each of isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving a mixture

Isomeric of both a starting material and an end product using various well known chromatographic methods.

When the stereochemistry of a disclosed compound is named or represented by structure, the named or represented stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight with respect to

10 other stereoisomers. When a single enantiomer is named or represented by structure, the named or represented enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by optically pure weight. The percentage of optical purity by weight is the ratio of the weight of the enantiomer to the weight of the enantiomer plus the weight of its optical isomer.

When a disclosed compound is named or represented by structure without indicating the stereochemistry, and the compound has at least one chiral center, it should be understood that the name or structure encompasses both the enantiomer of the free compound of the corresponding optical isomer, a racemic mixture of the compound , as enriched mixtures of an enantiomer with respect to its corresponding optical isomer.

When a disclosed compound is named or represented by structure without indicating stereochemistry and has at least two chiral centers, it should be understood that the name or structure encompasses a free diastereomer of other diastereomers, a pair of free diastereomers of other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which a diastereomer is enriched with respect to the other diastereomer (s) and mixtures of diastereomeric pairs in which a pair

25 diastereomeric is enriched with respect to the other diastereomeric pair (s).

As used herein, "substantially pure" means that the compound represented or named is at least about 60% by weight. For example, "substantially pure" may mean approximately 60%, 70%, 72%, 75%, 77%, 80%, 82%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%,

30 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.9%, or a percentage between 70% and 100%. In one embodiment, substantially pure means that the compound represented or named is at least about 75%. In a specific, substantially pure embodiment means that the compound represented or named is at least about 90% by weight.

Exemplification

Example 1: Synthesis of 2-aminoindoles by intermediates of 2-aminobenzophenone, by benzamide.

Scheme 1:

10 All solvents for reactions, extractions and chromatography were analytical grade. Dichloromethane, N, N-dimethylformamide, methanol and tetrahydrofuran were passed through an alumina column (A-2) and supported copper redox catalyst (Q-5 reactant). All other solvents, except ethanol (Pharmco-Aaper), were obtained from Aldrich. The solvents were used without further purification, except when indicated.

The reaction vessels were dried in an oven for at least 12 hours, and the reactions took place in both argon and nitrogen atmospheres. All reactions were magnetically stirred.

The reactions were monitored by thin layer chromatography (TLC) using silica gel plates 60, treated with 254 nm fluorescent dye (EMD) and by LC-MS (Waters 2690 Separations Module with Waters Micromass

20 LCT or Waters 2795 Separations Module with Waters Micromass ZQ). The exposed mass spectrometry data are from the LC-MS analysis.

Solvent evaporation was performed by rotary evaporation. Silica gel 60, 230-400 mesh (EMD) was used for purification by column chromatography. Ultrafast purification systems were also used

25 with associated previously loaded silica columns (Biotage Isolera and Teledyne Isco Companion).

1 H NMR spectra were recorded at 300 or 500 MHz in Bruker 300 and Varian I-500 NMR spectrometers, respectively. 13C NMR spectra were recorded at 126 MHz using a Varian I-500 NMR spectrometer. Chemical shifts in CDCl3, CD3OD, CD3CN and (CD3) 2O are reported in ppm, relative to CHCl3

30 (1 H NMR,  = 7.24 ppm; 13 C NMR,  = 77.23 ppm), CH 3 OH (1 H NMR,  = 4.87 ppm, 3.31 ppm; 13 C NMR,  = 49.15 ppm) , CH3CN (1H NMR,  = 1.94) and (CH3) 2O (1H NMR,  = 2.05). Coupling constants are provided in hertz. Attempts were made to be consistent with the NMR solvent; however, the variable solubilities of the compounds demanded the use of different solvents. Suitable solvents can be determined by those skilled in the art.

Example 2: Synthesis of 2-aminoindoles coupling aldehyde starting materials

Scheme 2:

5 All solvents for reactions, extractions and chromatography were of analytical quality. Dichloromethane, N, N-dimethylformamide, methanol and tetrahydrofuran were passed through an alumina column (A-2) and supported copper redox catalyst (Q-5 reactant). All other solvents, except ethanol (Pharmco-Aaper), were obtained from Aldrich. The solvents were used without further purification, except when indicated.

The reaction vessels were oven dried for at least 12 hours, and the reactions took place in both argon and nitrogen atmospheres. All reactions were magnetically stirred.

The reactions were monitored by thin layer chromatography (TLC) using silica gel plates 60, treated

15 with fluorescent dye at 254 nm (EMD) and by LC-MS (Waters 2690 Separations Module with Waters Micromass LCT or Waters 2795 Separations Module Micromass ZQ). The exposed mass spectrometry data are from the LC-MS analysis.

Solvent evaporation was performed by rotary evaporation. For purification by chromatography on

20 column silica gel 60, 230-400 mesh (EMD) was used. Ultra-fast purification systems with associated previously loaded silica columns (Biotage Isolera and Teledyne Isco Companion) were also used.

1 H NMR spectra were recorded at 300 or 500 MHz in Bruker 300 and Varian I-500 NMR spectrometers, respectively. 13C NMR spectra were recorded at 126 MHz using a Varian I-500 NMR spectrometer.

25 Chemical shifts in CDCl3, CD3OD, CD3CN and (CD3) 2O are reported in ppm, with respect to CHCl3 (1H NMR,  = 7.24 ppm; 13C NMR,  = 77.23 ppm), CH3OH (1H NMR ,  = 4.87 ppm, 3.31 ppm; 13 C NMR,  = 49.15 ppm), CH 3 CN (1 H NMR,  = 1.94) and (CH 3) 2 O (1 H NMR,  = 2.05) . Coupling constants are provided in hertz. Attempts were made to be consistent with the NMR solvent; however, the variable solubilities of the compounds demanded the use of different solvents.

Example 3: Synthesis of the 2-amino-5-ethynyl-3- {4- [3 (trifluoromethyl) diazirin-3-yl] phenyl} indole-3-ol bifunctionalized photoafinity probe

All solvents for reactions, extractions and chromatography were of analytical quality. Dichloromethane, N, N-dimethylformamide, methanol and tetrahydrofuran were passed through an alumina column (A-2) and supported copper redox catalyst (Q-5 reactant). All other solvents, except ethanol (Pharmco

10 Aaper), were obtained from Aldrich. The solvents were used without further purification, except when indicated.

The reaction vessels were oven dried for at least 12 hours, and the reactions took place in both argon and nitrogen atmospheres. All reactions were magnetically stirred.

The reactions were monitored by thin layer chromatography (TLC) using silica gel plates 60, treated with 254 nm fluorescent dye (EMD) and by LC-MS (Waters 2690 Separations Module with Waters Micromass LCT or Waters 2795 Separations Module Micromass ZQ). The exposed mass spectrometry data are from the LC-MS analysis.

The evaporation of the solvent was carried out by rotary evaporation. Silica gel 60, 230-400 mesh (EMD) was used for purification by column chromatography. Ultra-fast purification systems with associated previously loaded silica columns (Biotage Isolera and Teledyne Isco Companion) were also used.

1H NMR spectra were recorded at 300 or 500 MHz on Bruker 300 and Varian I-500 NMR spectrometers,

25 respectively. 13C NMR spectra were recorded at 126 MHz using a Varian I-500 NMR spectrometer. Chemical shifts in CDCl3, CD3OD, CD3CN and (CD3) 2O are reported in ppm, relative to CHCl3

(1 H NMR,  = 7.24 ppm; 13 C NMR,  = 77.23 ppm), CH 3 OH (1 H NMR,  = 4.87 ppm, 3.31 ppm; 13 C NMR,  = 49.15 ppm), CH3CN (1H NMR,  = 1.94) and (CH3) 2O (1H NMR,  = 2.05). Coupling constants are provided in hertz. Attempts were made to be consistent with the NMR solvent; however, the variable solubilities of the compounds demanded the use of different solvents.

5-Amino-5- [2- (trimethylsilyl) ethynyl] benzoic acid (14). 2-Amino-5-iodobenzoic acid (500 mg, 1.9 mmol, 1 eq.) Was dissolved in nitrogen degassed THF (10 ml) at room temperature. TMS-acetylene (0.34 ml, 2.5 mmol, 1.3 eq.), Nitrogen degassed triethylamine (0.8 ml, 5.7 mmol, 3 eq.), Dichlorobis (triphenylphosphine) palladium (II were added ) (267 mg, 0.4 mmol, 0.2 eq.) And copper iodide (145 mg, 0.8 mmol, 0.4 eq.), In order, to the reaction in the dark. Then, the reaction was stirred at room temperature for 20 minutes. The solvent was evaporated, and the residue was purified on a silica column (DCM / MeOH, 39: 1 → 19: 1) to yield 315 mg (71%) of the title compound as a dark orange solid. 1H NMR (500 MHz, CDCl3)  8.07 (d, J = 1.7, 1H, Ar-H), 7.37 (dd, J = 1.8, 8.6, 1H, Ar-H) , 6.57 (d, J = 8.6, 1H, Ar-H), 0.22 (s, 9H, SiC3H9). 13C NMR (126 MHz, CDCl3)  173.11 (COOH), 151.15 (C-Ar), 138.41 (C-Ar), 136.64 (C-Ar), 116.94 (C-Ar ), 111.06 (C-Ar), 109.23 (C-Ar), 104.98

15 (CSi (CH3) 3), 92.02 (CCSi (CH3) 3), 0.29 (Si (CH3) 3). Exact mass, 233.09. 231.7418 [M-H] -, 233.7569 [M + H] +.

2-amino-N-methoxy-N-methyl-5- [2- (trimethylsilyl) ethynyl] benzamide (15). 2-Amino-5- [2 (trimethylsilyl) ethynyl] benzoic acid (630 mg, 2.7 mmol, 1 eq.), HBTU (1.54 g, 4.0 mmol, 1.5 eq.) Were added and 4-methylmorpholine (0.74 ml, 6.7 mmol, 2.5 eq.), In order, to DMF (10 ml) and stirred at room temperature for 10 minutes. N, O-dimethylhydroxylamine hydrochloride (290 mg, 3.0 mmol, 1.1 eq.) Was then added to the reaction, and the reaction was stirred at room temperature for 16 hours. Water (20 ml) was then added, and the reaction was extracted three times with ethyl acetate (50 ml each time). To remove residual water, saturated sodium chloride (20 ml) was added to the organic phase, and the organic phase was separated and dried over sodium sulfate. The solvent was evaporated by rotary evaporation and the residue was purified on a silica column (hexanes / ethyl acetate,

3: 1) to produce 320 mg (43%) of the title compound as an orange solid. 1H NMR (500 MHz, CDCl3)  8.38 (d, J = 1.5, 1H, Ar-H), 7.82 (dd, J = 1.5, 7.5, 1H, Ar-H) , 7.10 (d, J = 7.3, 1H, Ar-H), 5.61 (s, 2H, NH2), 4.09 (s, 3H, OCH3), 3.66 (s, 3H, NCH3), 0.22 (s, 9H, Si (CH3) 3). 13C NMR (126 MHz, CDCl3)  169.20 (CON), 147.35 (C-Ar), 135.24 (C-Ar), 133.50 (C-Ar), 116.65 (C-Ar ), 116.55 (C-Ar), 111.21 (C-Ar), 105.40 (CSi (CH3) 3), 91.90 (CCSi (CH3) 3), 61.44 (NOCH3), 34 , 53 (NCH3), 0.29 (Si (CH3) 3). Exact mass, 276.13. 277,1046 [M + H] +.

2 - ({4- [3- (trifluoromethyl) diaziridin-3-yl] phenyl} carbonyl) -4- [2- (trimethylsilyl) ethynyl] aniline (16). 2-amino-Nmethoxy-N-methyl-5- [2- (trimethylsilyl) ethynyl] benzamide (403 mg, 1.5 mmol, 1 eq.) And 3- (4-bromophenyl) -3- (trifluoromethyl) were added -1,2bis (trimethylsilyl) diaziridine (synthesized by a 5-stage process: Bender et al., 2007, 599 mg, 1.5 mmol, 1 eq.) Together in a round flask and purged with nitrogen. THF was added, and the reaction was stirred at room temperature until all solids dissolved. The reaction was then cooled to -80 ° C in a diethyl ether / carbon snow bath, and 2.5 M n-butyllithium in hexanes (1.0 ml, 2.6 mmol, 1.8 eq .), causing the reaction to turn a dark red color. The reaction was stirred at -80 ° C for 2 hours and then quenched with saturated ammonium chloride solution (20 ml). The quenched reaction was extracted three times with ethyl acetate (50 ml each time). Then, the organic phase was dried over sodium sulfate, and the solvent was evaporated. Purification on silica column (hexanes / ethyl acetate, 3: 1 → 1: 1) produced 342 mg (58%) of the title compound as a yellow solid. 1H NMR (500 MHz, CDCl3) ,6 7.69 (dd, J = 8.2, 37.0, 4H, Ar-H), 7.50 (d, J = 1.8, 1H, Ar-H) , 7.37 (dd, J = 1.9, 8.6, 1H, Ar-H), 6.65 (d, J = 8.6, 1H, Ar-H), 6.32 (s, 2H , NH2), 2.88 (d, J = 8.6, 1H, CNH), 2.32 (d, J = 8.8, 1H, CNH), 0.18 (s, 9H, Si (CH3) 3). 13C NMR (126 MHz, CDCl3)  197.58 (CO), 151.25 (C-Ar), 141.43 (C-Ar), 138.23 (C-Ar), 138.06 (C-Ar ), 134.66 (C-Ar), 129.57 (C-Ar), 128.37 (q, C-Ar, J = 0.57), 123.55 (q, J = 278.40,

45 CF3), 117.35 (C-Ar), 117.19 (C-Ar), 110.28 (C-Ar), 104.90 (CSi (CH3) 3), 92.18 (CCSi (CH3) 3), 58.05 (q, J = 36.3, C (NH) 2), 0.25 (Si (CH3) 3). Exact mass, 403.13. 402,1046 [M-H] -, 404,1982 [M + H] +.

2 - ({4- [3- (trifluoromethyl) diazirin-3-yl] phenyl} carbonyl) -4- [2- (trimethylsilyl) ethynyl] aniline (17). 2 - ({4- [3 (trifluoromethyl) diaziridin-3-yl] phenyl} carbonyl) -4- [2- (trimethylsilyl) ethynyl] aniline (66 mg, 0.16 mmol, 1 eq.) Was dissolved in ether diethyl (10 ml) and manganese (IV) oxide (300 mg, 3.4 mmol, 21 eq.) was added to the solution. The reaction was stirred at room temperature for 30 minutes and then filtered through Celite with DCM to remove manganese (IV) oxide. The solvent was evaporated, and the residue was purified on a silica column (hexanes / ethyl acetate, 9: 1 → 2: 1), yielding 64 mg (97%) of the title compound as a yellow-orange solid. 1H NMR (500 MHz, CDCl3)  7.63 (d, J = 8.4, 2H, Ar-H), 7.46 (d, J = 1.7, 1H, Ar-H), 7.37 (dd, J = 1.8, 8.6, 1H, Ar-H), 7.28 (d, J =

55 8.2, 2H, Ar-H), 6.64 (d, J = 8.6, 1H, Ar-H), 6.30 (s, 2H, NH2), 0.18 (s, 9H, Yes (CH3) 3). 13C NMR (126 MHz, CDCl3)  197.20 (CO), 151.24 (C-Ar), 140.72 (C-Ar), 138.19 (C-Ar), 137.94 (C-Ar ), 132.27 (C-Ar), 129.59 (C-Ar), 126.48 (q, C-Ar, J = 1.19), 122.13 (q, J = 274.80, CF3 ), 117.35 (C-Ar), 117.10 (C-Ar), 110.28 (C-Ar), 104.86 (CSi (CH3) 3), 92.21 (CCSi (CH3) 3) , 28.62 (q, J = 40.69, CN2), 0.22 (Si (CH3) 3). Exact mass, 401.12, 399.7011 [M-H] -, 401.7108 [M + H] +.

2,2-dichloro-N- [2 - ({4- [3- (trifluoromethyl) diazirin-3-yl] phenyl} carbonyl) -4- [2- (trimethylsilyl) ethynyl] phenyl] acetamide (18). 2 - ({4- [3- (trifluoromethyl) diazirin-3-yl] phenyl} carbonyl) -4- [2- (trimethylsilyl) ethynyl] aniline (47 mg, 0.12 mmol, 1 eq.) Was dissolved in DCM (10 ml) and cooled to 0 ° C. Then dichloroacetyl chloride (0.013 ml, 0.14 mmol, 1.15 eq.) Was added, and the reaction was stirred at 0 ° C for 10 minutes. The reaction was then heated to room temperature and stirred for 30 minutes. The solvent was evaporated, and the residue was purified by silica column (hexanes / ethyl acetate, 3: 1), yielding 57 mg (94%) of the title compound as a yellow oil. 1H NMR (500 MHz,

CDCl3)  11.83 (s, 1H, CHCl2), 8.56 (d, J = 8.7, 1H, Ar-H), 7.76 (d, J = 9.1, 2H, Ar-H ), 7.69 (dd, J = 1.5, 8.8, 1H, Ar-H), 7.61 (d, J = 1.8, 1H, Ar-H), 7.32 (d, J = 8.2, 2H, Ar-H), 6.03 (s, 1H, NH), 0.19 (s, 9H, Si (CH3) 3). 13C NMR (126 MHz, CDCl3)  197.81 (Ar2-CO), 163.13 (NCOC), 139.23 (C-Ar), 138.79 (C-Ar), 138.33 (C-Ar ), 136.61 (C-Ar), 134.08 (C-Ar), 130.47 (C-Ar), 126.71 (q, J = 1.23, C-Ar), 123.41 ( C-Ar), 122.03 (q, J = 274.68, CF3), 121.60 (C-Ar), 120.94

5 (C-Ar), 103.04 (CSi (CH3) 3), 96.22 (CCSi (CH3) 3), 67.16 (CCl2), 28.64 (q, J = 40.83, CN2) , 0.03 (Si (CH3) 3). Exact mass, 511.05. 509.4841 [M-H] -, 511.5478 [M + H] +.

2-amino-3- {4- [3- (trifluoromethyl) diazirin-3-yl] phenyl} -5- [2- (trimethylsilyl) ethynyl] indole-3-ol (19). 2,2-Dichloro-N was dissolved

10 [2 - ({4- [3- (trifluoromethyl) diazirin-3-yl] phenyl} carbonyl) -4- [2- (trimethylsilyl) ethynyl] phenyl] acetamide (57 mg, 0.11 mmol, 1 eq. ) in EtOH (3 ml). Potassium cyanide (9.4 mg, 0.14 mmol, 1.3 eq.) In water (1 ml) was added to the reaction, and the reaction was stirred at room temperature for 16 hours. The EtOH was evaporated, and additional water (8 ml) was added. Then, the reaction was extracted three times with 5% isopropanol in DCM (20 ml each time), and the organic phase was dried over sodium sulfate. The solvent was evaporated, and the residue was purified on silica column.

15 (DCM / MeOH, 39: 1 → 19: 1 → 9: 1 → 4: 1) to produce 39.2 mg (82%) of the title compound as a yellow solid. 1H NMR (500 MHz, CD3OD) ,4 7.44 (d, J = 8.5, 2H, Ar-H), 7.29 (dd, J = 1.8, 8.8, 1H, Ar-H) , 7.22 (d, J = 8.3, 2H, Ar-H), 7.02-6.94 (m, 2H, Ar-H), 0.18 (s, 9H, SiC3H9). 13C NMR (126 MHz, CD3OD)  180.56 (C-NH2), 156.85 (C-Ar), 144.59 (C-Ar), 140.89 (C-Ar), 135.13 (C -Ar), 129.58 (C-Ar), 127.89 (d, J = 0.88, C-Ar), 127.66 (C-Ar), 126.99 (C-Ar), 123, 70 (q, J = 273.80, CF3), 117.82 (C-Ar), 116.69 (C-Ar), 107.08 (CSi (CH3) 3), 92.94 (CCSi (CH3) 3), 84.20 (Ar

20 COH), 29.55 (q, J = 40.25, CN2), 0.23 (Si (CH3) 3). Exact mass, 428.13. 426.6786 [M-H] -, 428.6918 [M + H] +.

2-amino-5-ethynyl-3- {4- [3- (trifluoromethyl) diazirin-3-yl] phenyl} indole-3-ol (20). 2-Amino-3- {4- [3 (trifluoromethyl) diazirin-3-yl] phenyl} -5- [2- (trimethylsilyl) ethynyl] indole-3-ol (30.5 mg, 0.07 mmol) , 1 eq.) In THF (5 ml) and

25 added 1M TBAF in THF (0.078 ml, 0.08 mmol, 1.1 eq.). The reaction was stirred at room temperature for 10 minutes. The solvents were then evaporated, and the residue was purified by silica column (DCM / MeOH,

39: 1 → 19: 1 → 9: 1 → 4: 1), producing 21.8 mg (86%) of the title compound as a yellow solid. 1H NMR (500 MHz, CD3OD) ,4 7.45 (d, J = 8.5, 2H, Ar-H), 7.33 (dd; J = 1.5, 8.0, 1H, Ar-H) , 7.23 (d, J = 8.2, 2H, Ar-H), 7.10 6.94 (m, 2H, Ar-H), 13C NMR (126 MHz, CD3OD)  180.61 (CNH2 ), 156.96 (C-Ar), 144.65 (C-Ar), 140.97 (C-Ar),

30 135.30 (C-Ar), 129.59 (C-Ar), 127.92 (d, J = 0.90, C-Ar), 127.76 (C-Ar), 127.02 (C -Ar), 123.73 (q, J = 273.90, CF3), 117.13 (C-Ar), 116.69 (C-Ar), 84.96 (CCH), 84.23 (Ar- COH), 77.31 (CCH), 29.56 (q, J = 40.35, CN2). Exact mass, 356.09. 354.7202 [M-H] -, 356.7268 [M + H] +.

Example 4: Synthesis of compound 1

Scheme 4

40 Representative procedures: Scheme 5

45 5-Chloro-2-aminobenzophenone (1.15.78 g, 68.1 mmol) and formic acid (200 ml) (117 ° C) were refluxed under argon for 24 h. After evaporating the excess formic acid, the obtained residue was loaded directly onto the silica gel column (0-30% EtOAc / Hexanes) which gave compound 2 (16.0 g, 90%) as a viscous oil yellow.

Scheme 6

5 A mixture of 2 (10.0 g, 38.5 mmol, 1.0 equiv) and KHCO3 (3.86 g, 38.5 mmol, 1.0 equiv) was dissolved in MeOH-H2O (1: 1, 100 ml) heating at 90 ° C (oil bath) for 15-20 min. The flask was removed from an oil bath and then KCN (3.26 g, 50.0 mmol, 1.3 equiv) was added. The reaction mixture was stirred at room temperature producing precipitate formation within 1 h. Stirring continued until the LC / MS showed the complete disappearance of 2 (2-3 h). Water was added to the reaction mixture and the solid was collected by

10 filtration and washed thoroughly with water. Recrystallization from acetonitrile (preferred) or ethanol gave the compound as a white solid (8.1 g, 81%).

Example 5: Representative synthesis for 2-aminoindoles

15 Scheme 7

Scheme 8

A microwave vial was loaded with 5-chloroisatin 1 (1 g, 1.0 equiv), 1-naphthylboronic acid 2 (1,895 g, 2.0 equiv), [(C2H4) 2Rh (acac)] (43 mg, 0 , 03 equiv, purchased from Strem), P (OPh) 3 (0.11 ml, 0.07 equiv), water (0.2 ml, 2.0 equiv) and 10 ml of acetone. Then, the reaction mixture was heated in microwave at 120 ° C for 1 h after the LC-MS analysis showed the completeness of the reaction. 1M HCl was added to the reaction and extracted twice with CH2Cl2. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a residue that recrystallized from acetone / hexanes giving 3 (1,490 g, 87%) as a gray solid. Instead of doing an aqueous processing, the reaction mixture can also be passed directly through a short pad of silica gel eluting with acetone and then concentration followed by recrystallization

30 as before.

Scheme 9

5 A microwave vial was loaded with 3 (300 mg, 1.0 equiv), TBDMS-NH2 4 (510 mg, 3.2 ml of the stock solution prepared below, 4.0 equiv), NMM (0.43 ml, 4.0 equiv) and 10 ml of dry THF under an argon atmosphere. To this mixture SnCl4 (1 M in CH2Cl2, 2 ml, 2.0 equiv) was added carefully. The mixture was heated in microwave at 110 ° C for 40 min. Ac HCl was added. 1 M and the reaction mixture was extracted with CH2Cl2 (1 x 40 ml) and twice with a mixture of CH2Cl2-i-PrOH (while the aq phase was saturated with NaCl). Then the extracts

10 organics were combined, dried over MgSO4, filtered, concentrated in vacuo and the residue obtained was dissolved in a minimum amount of CH2Cl2 and loaded directly onto the ISCO column (silica gel) (0-7% MeOH / CH2Cl2 containing 2% Et3N) and then recrystallization with CH2Cl2 / hexanes gave 5 (150 mg, yield: 50%) as an off-white solid.

15 Preparation of TBDMS-NH2 reagent 4

Ammonia gas (for 2-3 minutes) was bubbled through a solution of TBDMSCl (5 g) in 20 ml of THF at 0 ° C, which immediately caused the formation of NH4Cl precipitate. The cold bath was removed and the reaction mixture was then purged through an argon gas for 15-30 min to completely remove the ammonia without

20 react. The reaction mixture was filtered through a syringe-free filter and washed thoroughly with THF so that the final volume of the TBDMS-NH2 containing solution was 24 ml. The reaction yield was assumed to be 90% (3.9 g) and this solution was stored at room temperature under an argon atmosphere and used in the previous reaction without further purification.

25 Example 6: Representative synthesis of 2-aminoindoles

Scheme 10:

Representative procedures: Scheme 11:

5 A 20 ml capacity microwave vial was loaded with PdCl2 (0.05 equiv, 24 mg), P (1-naphthyl) 3 (0.05 equiv, 56 mg), boronic acid 2 (2.0 equiv, 1,153 g), aldehyde 1 (1.0 equiv, 500 mg), K2CO3 (3.0 equiv, 1,117 g) and dry THF (12 ml). The vial was closed and purged with N2 for 5-10 min. The reaction mixture was heated at 65 ° C for 15 h, cooled to room temperature. Water was added and the reaction mixture was extracted with EtOAc (3 x 40 ml). The combined EtOAc extracts were dried over MgSO4, filtered, concentrated in vacuo and the residue obtained

10 was dissolved in minimal amount of CH2Cl2 and loaded directly onto the ISCO column (silica gel) (0-20% EtOAc / hexanes) which gave diaryl methanol 3 (500 mg, yield: 52%) as a light yellow oil.

Scheme 12:

Diarylmethanol 3 (1.0 equiv, 460 mg) was dissolved in 20 ml of CH2Cl2 and to this solution was added activated MnO2 (16.0 equiv, 1.80 g). The reaction mixture was stirred under a nitrogen atmosphere at room temperature for 4 h, after which the LC-MS analysis showed the completeness of the reaction. The reaction mixture was filtered over

20 Celite and washed thoroughly with methanol and CH2Cl2. The solvents were evaporated in vacuo to give diaryl ketone 4 (392 mg, yield: 86%) as a light yellow oil that was used in the next step without further purification.

Scheme 13:

A mixture of 4 (390 mg, 1.0 equiv), SnCl2 · 2H2O (5.0 equiv, 1,244 g), a few drops of conc. HCl was heated in the microwave. and 15 ml of EtOH at 130 ° C for 30 min. The LC-MS analysis showed the completeness of the reaction. It was found that the presence of HCl takes the reaction to completeness faster than without it (the reaction can also

30 be carried out under conventional heating, that is, at the reflux temperature of EtOH). The solvent was evaporated in vacuo and the residue obtained was dissolved in a minimum amount of CH2Cl2 and loaded directly onto the ISCO gel column (silica gel) (0-1% MeOH / CH2Cl2) which gave 2-aminobenzophenone 5 (321 mg, yield: 90%) as a light yellow oil.

The nitro group can also be reduced under hydrogenation conditions as long as the functional groups present in the molecule are stable to the conditions mentioned above. For example:

Scheme 14:

To a solution of diaryl ketone 8 (600 mg) in 20 ml of EtOH was added 100 mg of 10% Pd / C. The reaction mixture was evacuated using domestic vacuum and then introduced an H2 balloon into the flask. The mixture is

10 stirred at room temperature for 2 h (or until LC-MS showed the completeness of the reaction). After completeness, the reaction mixture was filtered over Celite, washed with MeOH and concentrated in vacuo to afford 9 (441 mg, 81%) as a yellow viscous oil that was used in the next step without further purification.

Scheme 15: 15

2-Aminobenzophenone 5 (321 mg, 1.0 equiv) and formic acid (20 ml) (117 ° C) were refluxed under argon for 24 h. After evaporating the excess formic acid, the residue obtained was dissolved in a minimum amount of CH2Cl2 and loaded directly onto the ISCO column (silica gel) (0-30% EtOAc / hexanes) which gave 6 (310 mg, yield: 89%) as a light yellow oil.

Scheme 16:

A mixture of 6 (310 mg, 1.0 equiv) and KHCO3 (89 mg, 1.0 equiv) was dissolved in MeOH-H2O (1: 1, 6 ml) by heating at 70 ° C (oil bath) for 10- 15 min. The flask was removed from an oil bath and then KCN (75 mg, 1.3 equiv) was added. The reaction mixture was stirred at room temperature overnight. Agitation continued

30 until LC / MS showed the complete disappearance of 6. Water was added to the reaction mixture producing the solid formation that was collected by filtration, washed with water and hexanes to give aminoindole 7 (220 mg, yield: 71 %) as a white solid.

(Important: If the addition of water does not cause precipitate formation, then the mixture can be extracted with

CH2Cl2 and once with a mixture of i-PrOH-CH2Cl2 (saturating the ac phase with NaCl). The organic extracts were then combined, dried over MgSO4, filtered, concentrated in vacuo and then the

recrystallization with CH2Cl2 / hexanes would provide pure aminoindole).

Example 7: Representative synthesis of 2-aminoindoles

Scheme 17

Representative procedures: 10 Scheme 18:

To a solution of N, O-dimethylhydroxylamine hydrochloride (1.5 equiv, 2.962 g) in 90% EtOH aq. (45 ml of EtOH and 5 ml of H2O) Et3N (1.5 equiv, 4.23 ml) was added, and after 10 min stirring at room temperature,

15 5-Chloroisatoic anhydride 1 (1.0 equiv, 4 g) was added portionwise. The reaction was then heated at reflux for 90 min and poured into an equal volume of ice and aq NaHCO3. sat. and extracted with EtOAc (3 x 100 ml). The combined EtOAc extracts were dried over MgSO4, filtered, concentrated in vacuo and the residue obtained was dissolved in a minimum amount of CH2Cl2 and loaded directly onto the ISCO column (silica gel) (0-2.5% of MeOH / DCM) which gave 2 (2.6 g, yield: 60%) as a light brown solid.

20 Scheme 19:

At a cooled mixture (-80 ° C, carbonic snow / Et2O) of 2 (0.577 g, 1.0 equiv) and bromide 3 (0.650 g, 1.0 equiv) in

30 ml of dry THF under an argon atmosphere was added n-BuLi (2.5 M in hexanes, 2.2 ml, 2.05 equiv) dropwise. The mixture was stirred at the same temperature for 30 min and quenched with aq HCl. 1 M and extracted with EtOAc (3 x 50 ml). The combined EtOAc extracts were dried over MgSO4, filtered, concentrated in vacuo and the residue obtained was dissolved in a minimum amount of CH2Cl2 and loaded directly onto the ISCO column (silica gel) (0-30% EtOAc / hexanes ) which gave 4 (0.542 g, yield: 64%) as a yellow solid.

See Example (Scheme) for formylation and cyclisation procedures.

Example 8: Synthesis of 2-aminoindoles from isatins

Scheme 20:

Example 9: Synthesis of 2-aminoindoles from oxindoles

Scheme 21:

Scheme 22:

Example 11: Alternative synthesis of compound 1

Scheme 23:

15 Scheme 24:

Scheme 25:

Scheme 25b:

Compound 225 was synthesized after four stages: Scheme 26:

Experimental part 10 Stage 1

Scheme 27:

A mixture of SM (1.6 g, 8 mmol), iodoethane (1.37 g, 8.8 mmol) and K2CO3 (1.21 g, 8.8 mmol) was dissolved in DMF (10 ml) and the The mixture was stirred at 70 ° C under N2, overnight. The reaction mixture was diluted with H2O and extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, concentrated in vacuo. The residue was purified by silica gel column chromatography (PE) to give (1.5 g, 87%) as a liquid.

Stage 2

Scheme 28:

To a solution of a (1.5 g, 6.88 mmol) and 2-amino-5-chloro-N-methoxy-N-methylbenzamide (1.34 g, 6.26 mmol) in anhydrous THF (40 ml) at -78 □ under N2 n-BuLi (2.5 M in hexane, 7.0 ml, 17.5 mmol) was added dropwise. The resulting solution was stirred for 1 h at the same temperature, then quenched with aq NH4Cl. 30 saturated and extracted with ethyl acetate (3 x 100 ml). The organic phases were separated, combined, dried (Na2SO4) and concentrated to give a residue, which was purified by flash chromatography on silica gel.

(PE: EA = 20: 1) giving b (1.1 g, 54%).

Stage 3

Scheme 29:

A mixture of acetic anhydride (6 ml) and formic acid (3 ml) was heated at 50 □ with stirring for 2 h, then cooled to rt. The resulting solution was added to a mixture of b (1.1 g, 3.75 mmol) in THF (4-10 ml). After stirring the mixture at rt overnight, the solution was diluted with H2O. The solid formed was filtered and washed with hexane to give c (1.05 g, 87%), which was used for the next step without further purification.

Stage 4

15 Scheme 30

A mixture of c (1.05 g, 3.27 mmol), KHCO3 (327 mg, 3.27 mmol) and KCN (638 mg, 9.81 mmol) was stirred in

20 methanol / water (15 ml / 5 ml) for 3 h at room temperature. After classical processing, the residue was purified by silica gel column chromatography (DCM / methanol) and then recrystallized from hexane / methanol to give compound 225 (600 mg, 57%).

Example 15: Representative Synthesis of Compound 142

Summary

The synthesis of compound 142 was shown in the synthesis scheme. It was synthesized by reacting 2-bromo-4-fluorophenol with ethyl iodide. It was then reacted with 2-amino-5-chloro-N-methoxy-N

30-methylbenzamide giving b, which was reacted with formic acid to provide c. Finally, c was reacted with potassium cyanide to provide compound 142.

Scheme 31:

5

Experimental part

Stage 1

10

Scheme 32:

To a solution of 2-bromo-4-fluorophenol (1.9 g, 10 mmol) in DMF (10 ml) was added K2CO3 (1.52 g, 11 mmol) and ethyl iodide (1.72 g, 11 mmol ). The resulting mixture was stirred for 24 h at room temperature. The reaction mixture was diluted with H2O (40 ml) and extracted with hexane. The organic phase was washed with water, dried, filtered on a plug of silica gel and concentrated to give (1.85 g, 85%) as a colorless oil.

Stage 2

20 Scheme 33:

To a mixture of a (1.85 g, 8.5 mmol) and 2-amino-5-chloro-N-methoxy-N-methylbenzamide (1.82 g, 8.5 mmol) in 30

25 ml of dry THF under an atmosphere of N2 n-BuLi (2.5 M in hexanes, 10.0 ml, 25 mmol) was added dropwise at 78 ° C. The resulting mixture was stirred at the same temperature for 1 h, quenched with aqueous ammonium chloride and extracted with EtOAc (3 x 100 ml). The combined organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (hexanes: EtOAc = 10: 1) to give b (1.0 g, 40% ) as a yellow solid.

Stage 3

Scheme 34:

A solution of 2 ml of formic acid and 4 ml of acetic anhydride was heated at 50 ° C for 2 h giving the formic acetic anhydride and then cooled to room temperature. To a solution of b (600 mg) in 10 ml of THF was added the formic acetic anhydride (6 ml) prepared in situ. The resulting mixture was stirred at

10 room temperature for 3 h. After completion of the reaction (CCF monitoring), the solution was diluted with water (50 ml) and filtered under vacuum giving c (900 mg, 90%) as a yellow solid, which was used for the next step without further purification. .

Stage 4

15 Scheme 35:

20 A microwave vial was loaded with c (500 mg, 1.6 mmol), KCN (202 mg, 3.2 mmol) and MeOH / H2O (v / v = 1/1, 10 ml). The resulting mixture was heated under microwave at 75 ° C for 30 min and cooled to room temperature. The reaction solution was filtered under vacuum and the solid obtained was recrystallized from methanol to give compound 142 (199 mg, 40%).

Example 16: Representative Synthesis of Compound 201

Summary

Compound 201 was synthesized by a seven-stage route depicted below. 30 Scheme 36

Experimental part Stage 1

Scheme 37

To a solution of 3-bromo-2-chloro-5-nitropyridine (23.5 g, 100 mmol) in 200 ml of CH3OH was added CH3ONa (54 g, 1.0 mol) with stirring in an ice bath. The resulting solution was heated at 80 ° C for 12 h and cooled to room temperature. The reaction mixture was diluted with 200 ml of H2O and extracted with ethyl acetate (3 x 250 ml). The organic phase was dried over magnesium sulfate, filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (50: 1, petroleum ether / EtOAc) to give (6.8 g, 34

15%) as a yellow oil.

Stage 2

Scheme 38 20

To a solution of a (6.8 g, 29 mmol) in 78 ml of EtOH and 10 ml of H2O was added 0.8 ml of conc. HCl. and iron powder (49 g, 174 mmol) with stirring. The resulting solution was heated at 80 ° C under a nitrogen atmosphere for 3 h and cooled to room temperature. The reaction mixture was filtered and the filtrate was concentrated to provide b (5.1 g, 86%) as a brown-yellow residue, which was used directly for the next step.

Stage 3

30 Scheme 39:

A solution of b (5.1 g, 25 mmol) in 22 ml conc. H2SO4. and 28 ml of H2O was added dropwise

35 solution of NaNO2 (1.75 g, 25 mmol) in 5 ml of H2O at 0 ° C with stirring. The resulting mixture was stirred at 0 ° C for 1 h, and then added dropwise to 34 ml of 50% aqueous solution of H2SO4 at reflux. The reaction mixture was stirred at reflux for 2 h, cooled to room temperature, neutralized with 3 N aqueous NaOH solution at pH = 6 under an ice bath and extracted with EtOAc (3 x 150 ml). The organic phase was dried, filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (50: 1,

CH2Cl2 / MeOH) giving c (1.16 g, 23%) as a white solid.

Stage 4

Scheme 40:

To a solution of c (1.16 g, 5.68 mmol) and K2CO3 (2.3 g, 17 mmol) in 35 ml of DMF was added a portion of CH3I (2.0 g, 14 mmol) under an atmosphere of nitrogen at 0 ° C with stirring. The resulting solution was heated at 50 ° C for 1 h, cooled to room temperature, diluted with 100 ml of water and extracted with DCM (3 x 70 ml).

The organic phase was dried (Na2SO4), filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (50: 1, petroleum ether / EtOAc) to give d (1.1 g, 89 %) as a yellow liquid.

Stage 5

15 Scheme 41:

To a solution of d (1.1 g, 5 mmol) and 2-amino-5-chloro-N-methoxy-N-methylbenzamide (1.0 g, 5 mmol) in THF

Anhydrous (30 ml) n-BuLi (1.6 M in hexane, 9.5 ml, 15 mmol) was added dropwise at -78 ° C under a nitrogen atmosphere with stirring. The resulting solution was stirred at -78 ° C for 3 h, quenched with 50 ml of saturated aqueous NH4Cl solution and extracted with DCM (3 x 70 ml). The organic phase was dried (Na2SO4), filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (20: 1, petroleum ether / EtOAc) giving e as a yellow solid (530 mg, 36%)

Stage 6

Scheme 42:

To a solution of e (530 mg, 1.8 mmol) in 5 ml of THF at room temperature was added 6 ml of formic acetic anhydride solution, which was prepared by stirring a mixture of acetic anhydride (4 ml) and formic acid (2 ml) (note that the ratio of acetic anhydride volume and formic acid volume is 2: 1) to 50

35 ° C for 2 h and cooled to room temperature. The resulting solution was stirred at room temperature for 2 h, diluted with 50 ml of H2O and filtered to provide a yellow solid, which was washed with hexane and dried in vacuo to afford f (530 mg, 95%), which was used. directly to the next stage.

Stage 7

Scheme 43:

To a mixture of f (530 mg, 1.65 mmol) and KHCO3 (404 mg, 4 mmol) in MeOH-H2O (v / v = 1/1, 15 ml) was added KCN (263 mg, 4 mmol) of A portion with stirring. The resulting solution was heated at 80 ° C for 30 min, cooled to room temperature, diluted with 100 ml of water and extracted with DCM (3 x 70 ml). The organic phase

10 was dried (Na2SO4), filtered and concentrated to give a residue, which was purified by column chromatography on silica gel (30: 1, DCM / methanol) to provide compound 201 (130 mg, 25%) as a solid. White.

15 Scheme 43:

Experimental part

20 Starting materials, reagents and solvents were obtained from commercial suppliers and were used without further purification. NMR spectra were obtained using a Bruker 400 instrument. 1 H spectra were measured with reference to an internal standard of tetramethylsilane at 0 ppm. HPLC analysis was performed using Agilent 1100 with 3.5 µ Extend-C18 Zorbax column (4.6 x 50 mm). Mobile phase consisting of solvent A, 0.1%

25 of trifluoroacetic acid in water, solvent B, 0.1% of trifluoroacetic acid in MeCN. The gradient was 10 -90% of mobile phase B in 4 minutes. A = 210, 254 nm. 2-Amino-5-chlorobenzoic acid [635-21-2] was ordered from AK Scientific, Inc, order number: 765381. 2-Bromo-4-fluorophenol [496-69-5] was ordered from Oakwood Products , Inc, order number: 004231.

Step 1. Preparation of 6-chloro-2-methyl-4H-benzo [d] [1,3] oxazin-4-one

A mixture of 2-amino-5-chlorobenzoic acid (90 g, 524 mmol) and acetic anhydride (160 ml) was heated under reflux under nitrogen for 3 hours. The reaction became a solution during heating. The reaction was cooled to room temperature. Some solid precipitated during this period of time. The reaction mixture was suspended in 1 L of IPA and filtered. The solid was washed with more IPA (50 ml) and dried under vacuum at room temperature for 18 hours. The product was collected as a solid (91 g, yield: 89%). 1H NMR (CDCl3): 8.14 (d, J = 6 Hz, 1H), 7.73 (dd, J = 21 Hz, 6 Hz, 1H), 7.50 (d, J = 21 Hz, 1 H ), 2.47 (s, 3H).

Stage 2 Preparation of 2-ethoxy-4-fluorophenyl bromide

2-Bromo-4-fluorophenol (105 g, 550 mmol), ethyl iodide (110 ml, 1.37 mol) and potassium carbonate (190 g) in acetone (400 ml) were stirred vigorously at 55 ° C under nitrogen during nitrogen. 4 hours. The reaction was cooled to room temperature and filtered. The solid was washed with more acetone (50 ml). The filtrate was concentrated on a rotary evaporator to remove most of the acetone (some solid precipitated). MTBE (600 ml) was added. The mixture was stirred for 3 minutes and filtered. The filtrate was concentrated to give a clear oil (117 g, yield: 97%). 1H NMR (CDCl3): 7.28 (m, 1H), 6.96 (m, 1H), 6.83 (m, 1H), 4.05 (qt, J = 18 Hz, 2H), 1.45 (t, J = 18 Hz, 3H).

Step 2. Preparation of N- (4-chloro-2- (2-ethoxy-5-fluorobenzoyl) phenyl) acetamide

Preparation of Grignard reagent: A solution of 2-ethoxy-4-fluorophenyl bromide (30 g, 138 mmol) in THF (140 ml) was added dropwise to a mixture with magnesium flake stirring and catalytic amount of iodine low nitrogen The resulting mixture was heated at reflux for 15 minutes and cooled to room temperature (Grignard reagent). In a separate flask, 6-chloro-2-methyl-4H-benzo [d] [1,3] oxazin-4-one (25 g, 128 mmol) was dissolved in THF (200 ml) and stirred under nitrogen. Grignard reagent was transferred slowly to the flask for 30 minutes. The reaction temperature was maintained below 55 ° C during the addition. The resulting mixture was stirred for an additional 2 hours under nitrogen. The reaction was quenched by the slow addition of aqueous ammonium chloride solution (30 g / 300 ml). The reaction was extracted in MTBE (500 ml). The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated on a rotary evaporator to give a solid. The solid was sonicated for 5 minutes in ethyl acetate (250 ml) and filtered. The filtrate was concentrated on a rotary evaporator to approximately 70 ml and cooled to -20 ° C for 4 hours. During this time, crystallized product precipitated and was collected by filtration (25 g, yield: 58%). 1H NMR (CDCl3): 11.2 (a, 1H), 8.73 (d, J = 22 Hz, 1H), 7.49 (dd, J = 24 Hz, 7 Hz, 1H), 7.38 ( d, J = 6 Hz, 1H), 7.2 (m, 1H), 7.07 (dd, J = 20 Hz, 8 Hz, 1H), 6.93 (m, 1H), 3.97 (q , J = 17 Hz, 2H), 2.27 (s, 1H), 1.13 (tr, J = 17 Hz, 3H).

Step 3. Preparation of (2-amino-5-chlorophenyl) (2-ethoxy-5-fluorophenyl) methanone

N- (4-Chloro-2- (2-ethoxy-5-fluorobenzoyl) phenyl) acetamide (25 g) was refluxed in a solution of concentrated HCl (6.5 ml) and ethanol (200 ml) for 3 hours . The resulting mixture was basified by adding aqueous sodium carbonate and extracted into MTBE (500 ml). The MTBE phase was washed with brine and dried (Na2SO4), filtered and concentrated to give an oil (20 5 g, yield: 94%). 1H NMR (CDCl3): 7.20 (m, 2H), 7.11 (m, 1H), 7.00 (dd, J = 20 Hz, 8 Hz, 1H), 6.91 (dd, J = 23 Hz, 10 Hz, 1H), 6.65 (m, 1H), 6.34 (a, 1H), 3.39 (q, J = 18 Hz, 2H), 1.19 (tr, J = 18 Hz , 3H).

Step 4. Preparation of N- (4-chloro-2- (2-ethoxy-5-fluorobenzoyl) phenyl) formamide

A mixture of (2-amino-5-chlorophenyl) (2-ethoxy-5-fluorophenyl) methanone (20.5 g, 70 mmol), zinc oxide (3 g, 37 mmol) and formic acid (28, 5 ml, 740 mmol) under nitrogen at 55 ° C for 4 hours with vigorous stirring. The resulting mixture was cooled to room temperature. DCM (250 ml) was added. The reaction was filtered. The filtrate was washed with water (200 ml x 2), sat. NaHCO3. (200 ml), brine (100 ml), dried (Na2SO4), filtered and concentrated to give a yellow solid (20 g, yield: 89%). 1H NMR (CDCl3): 11.10 (a, 1H), 8.73 (a, J = 22 Hz, 1H), 8.53 (s, 1H), 7.51 (dd, J = 22 Hz, 6 Hz, 1H), 7.41 (d, J = 6 Hz, 1H), 7.20 (m, 1H), 7.10 (dd, J = 19 Hz, 7 Hz, 1H), 6.93 (dd , J = 22 Hz, 10 Hz, 1H), 3.96 (q, J = 18 Hz, 2H), 1.13 (tr, J = 18 Hz, 3H). 1 H NMR and HPLC of N- (4-chloro-2- (2-ethoxy-5-fluorobenzoyl) phenyl) formamide.

Step 5. Preparation of compound 142, 2-amino-5-chloro-3- (2-ethoxy-5-fluorophenyl) -3H-indole-3-ol

N- (4-Chloro-2- (2-ethoxy-5-fluorobenzoyl) phenyl) formamide (20 g, 62.5 mmol) was dissolved in hot methanol (300 ml). Water (200 ml) (precipitate) was added. The mixture was stirred for 2 minutes. Potassium carbonate (6.8 g, 69 mmol) was added to the mixture with stirring and stirred for 2 minutes. Potassium cyanide (4.6 g, 81 mmol) was added to the reaction with stirring. The mixture was stirred at room temperature for 18 hours and stirred at 70 ° C (bath) for 4 hours. The reaction was cooled to room temperature and poured into water (400 ml), stirred and filtered. The solid was dried in a vacuum oven at room temperature. The solid was suspended in hot chloroform (200 ml, bath temperature: 55 ° C) for 10 minutes and filtered. The solid was collected and dried (16 g, yield: 80%). 1H NMR (CDCl3): 7.72 (dd, J = 24 Hz, 8 Hz, 1H), 7.13 (dd, J = 20 Hz, 6 Hz, 1H), 7.00 (m, 1H), 6 , 91 (d, J = 20 Hz, 1H), 6.80 (dd, J = 22 Hz, 10 Hz, 1H), 6.76 (d, J = 5 Hz, 1H), 4.85 (a, 3H), 3.78 (m, 1H), 3.58 (m, 1H), 3.31 (q, J = 17 Hz, 2H), 0.97 (tr, J = 17 Hz, 3H). 1 H NMR and HPLC of compound 142, 2-amino-5-chloro-3- (2-ethoxy-5-fluorophenyl) -3 Hindol-3-ol

Example 18: Chiral separation of racemic compound 142 using supercritical fluid chromatography (SFC)

This example describes a procedure to solve racemic compound 142 in its enantiomers, compounds 266 and 267, by supercritical fluid chromatography (SFC). The racemic synthesis was carried out as described in Example 17 by WuXi PharmaTech. The amorphous material isolated from the SFC crystallized giving a crystalline material that was fully characterized.

1. Separation method:

SFC and HPLC were used for analytical separation and SFC was used for preparative chiral separation.

1.1 Analytical separation method:

SFC-EM

Instrument: Analytical CFS Berger Analix with DAD detector Column: ChiralPak AD-3, 150 x 4.6 mm ID Mobile phase: A for SFC CO2 and B for 2-propanol (0.05% DEA) Gradient: B 25 % Flow rate: 2.4 ml / min Wavelength: 220 nm

HPLC

Instrument: Shimadzu LC-20A with DAD detector Column: Shim-pack XR-ODS 30 mm x 3 mm ID Mobile phase: A for H2O (0.1% TFA) and B for acetonitrile Gradient: B 10-80% Flow rate: 1.2 ml / min Wavelength: 210 nm and 254 nm

1.2 Preparative separation method

Instrument: Preparatory CFS Berger MGIII Column: ChiralPak AD-H, 250 x 30mm ID Mobile phase: A for SFC CO2 and B for 2-propanol Gradient: A: B 70:30 Flow rate: 80 ml / min Sample preparation : dissolved in ethanol, 50 mg / ml Injection: 4 ml per injection. After separation, the fractions were dried by rotary evaporator at bath temperature 40 ° C.

2. Crystallization:

To the separated enantiomer A and B, ethyl ether was added in the amount of 50 ml / g, respectively. Stir in a bath at 30 ° C to ensure that the solid dissolved. The solution was transferred to wide mouth bottles. Put the bottles in the ventilated hood to allow the ethyl ether to evaporate at a controlled speed. With the solvent evaporated slowly, crystals separated from the crystallization waters can be seen. Filter and wash the solid with ethyl ether for three times giving the enantiomer A and B (crystal), respectively. The crystallization waters were concentrated by the rotary evaporator to achieve the enantiomer A and B (crystallization waters) respectively.

The enantiomer A and B (crystal) were ground and dried respectively in a vacuum oven at 30 ° C for 24 h to remove residual ethyl ether.

3. Quality control:

3.1 Proof of e.e. by SFC-EM

The test was carried out under the same conditions as shown in 1.1

3.2 Purity test using HPLC and NMR

The test was carried out under the same conditions as shown in 1.1

5 3.3 Analysis of X-RPD and DSC

4. Note:

During the entire process, only ethanol, 2-propanol and ethyl ether were used.

Table 2: Results of the chiral separation of compound 142

Description

Weight (g) e.e. (%) Purity (%)

Enantiomer A, isomer that elutes faster by SFC in AD-H column (crystal)

29.6 99.3 99.16 (210 nm) 98.77 (254 nm)

Enantiomer A, isomer that elutes faster by SFC in AD-H column (crystallization waters)

14.6 97.9 96.12 (210 nm) 90.78 (254 nm)

Enantiomer B, isomer that elutes slower by SFC in AD-H column (crystal)

24.5 98.9 100.0 (210 nm) 100.0 (254 nm)

Enantiomer B, isomer that elutes slower by SFC in AD-H column (crystallization waters)

20.5 95.5 96.44 (210 nm) 97.86 (254 nm)

Example 19: The selected aminoindole compounds of the invention demonstrate potency in vitro against different Plasmodium species

In vitro potency against P. falciparum:

In vitro potency against P. falciparum was evaluated using a modified version of the method of Plouffe et al. (Plouffe, D., A. Brinker, C. McNamara, K. Henson, N. Kato, K. Kuhen, A. Nagle, F. Adrian, JT 20 Matzen, P. Anderson, TG Nam, NS Gray, A. Chatterjee, J. Janes, SF Yan, R. Trager, JS Caldwell, PG Schultz, Y. Zhou and EA Winzeler 2008. In silico activity profiling reveals the mechanism of action of antimalarials discovered in a highthroughput screen. Proc Natl Acad Sci USA 105: 9059-64). The parasites were cultured in the presence of a drug in RPMI (Sigma) containing 4.16 mg / ml of Albumax in a total volume of 50 µl to 2.5% hematocrit and an initial parasitemia of 0.3% in black plaques light background Greiner GNF. The crops are

25 incubated 72 h at 37 ° C under 95% N2, 4% CO2 and 3% O2. At the end of the incubation, SYBR Green was added at a dilution of 1: 10,000 and the plates were stored overnight (or until ready to be read) at -80 ° C. Just before reading, the plates were centrifuged at 700 rpm and the fluorescence was read using 480 nm excitation frequency and 530 nm emission. Compound concentrations that inhibit parasite replication reduce the fluorescence intensity of SYBR Green bound to the parasite's DNA.

30 The results show that many aminoindoles have potent IC50 values (inhibitory concentration that reduces parasitemia by 50%) in the low double-digit nanomolar range with respect to P. falciparum 3D7, Dd2 and HB3 strains (not shown). IC50 values were determined by staining the parasites with staining for DAPI and / or SYBR Green nucleic acids. The ranges of IC50 values with respect to strain 3D7 of P.

Falciparum for various compounds of the invention are indicated in Table 1 using asterisks (see the legend of Table 1).

In vitro potency against P. knowlesi:

40 Selected compounds were tested against P. knowlesi strain H1 parasites cultured in Rhesus blood cells as a substitute for P. vivax infections using the method of Kocken et al. (Kocken, CH, H. Ozwara, A. van der Wel , AL Beetsma, JM Mwenda, and AW Thomas. 2002. Plasmodium knowlesi provides a rapid in vitro and in vivo transfection system that enables double-crossover gene knockout studies. Infect Immun 70: 655-660). Briefly, P. knowlesi were grown in 2% of Rhesus macaque erythrocytes

45 (New England Primate Research Center) in RPMI culture medium containing 10% human O + serum (Interstate Blood Bank). Parasites were purified in the schizont stage by flotation in 60% Percoll (GE life sciences) and allowed to reinvade to generate a simultaneous population of parasites in the ring stage. Trials were conducted with drugs sowing parasites in the 0.5% ring stage of triplicate parasitemia, in RPMI containing 2.5 µg / ml hypoxanthine. The parasites were incubated for 24 hours with compounds of

50 tests diluted successively. After 24 hours, fine extensions were made to confirm that the reinvasion had occurred, 0.5 µCi of 3H-labeled hypoxanthine (Perkin Elmer) was added to each well, and the parasites were allowed to advance through phase S to early skizontes. Next, the cells were collected by glass filter plates and the incorporation of 3H was measured by scintillation counting. The values were normalized to control percentages that do not contain drug, and IC50 values were generated

55 (GraphPad Prism®). The results are shown in Table 3.

Table 3. Power and selectivity in vitro

Power (IC50; nM)

Selectivity

Plasmodium spp.

Mammalian cytotoxicity (IC50; µM) hERG (µM)

Compound No.

Pd Dd2 Pf 3D7 Pk H1 Pb ANKA Dermal fibroblast Epithelial kidney Lisis Eritr. CHO

one

285 200 336 1560 > 242 > 242 > 155 > 25

2

1,460 665 ND 1363 > 242 > 242 > 155 ND

3

675 313 ND 1689 > 242 > 242 > 155 ND

eleven

37 30 ND ND 24 24 > 129 ND

37

455 183 318 ND > 62.5 > 62.5 > 168 ND

38

110  38 ND ND > 62.5 > 62.5 > 147 ND

39

347 108 190 2987 > 62.5 > 62.5 > 178 ND

146

37 22 90 ND > 188 > 188 > 120 19

202

81 twenty-one ND ND > 195 > 195 > 125 ND

142

49 2. 3 38 ND > 195 > 195 > 125 twenty-one

266

58 18 ND 342 > 195 > 195 > 125 ND

267

65 28 26 331 > 195 > 195 > 125 36.6

Legend of Table 3: Pf Dd2: Plasmodium falciparum strain Dd2; PF 3D7: P. falciparum strain 3D7; Pk H1: P. knowlesi strain H1; Pb ANKA: P. berghei strain ANKA; Dermal fibroblast: normal human dermal fibroblasts 5 (Clonetics No. CC-2509); Epithelial kidney: normal human renal proximal tubules (Clonetics No. CC-2553); Erythro Lysis: Erythrocyte lysis; CHO: Chinese hamster ovary cells.

Example 20: The aminoindole compounds selected from the invention demonstrate efficacy in vivo against P. berghei and P. falciparum in mice

Efficacy in vivo against P. berghei in mice:

Plasmodium species that infect humans (such as P. falciparum, P. vivax, P. knowlesi) do not infect or cause disease in rodents and can only be directly evaluated in infection primate models. 15 Due to ethical issues and costs, the acute P. berghei rodent model is considered the “gold standard” for assessing antimalarial efficacy in animal models. This model is adapted from Peters' 4-day suppressor test (Peters, W. 1987. Chemotherapy and Drug Resistance in Malaria, p. 102-115, 2 ed, vol. 1. Academic Press, Orlando, FL .; Peters, W. 1975. The chemotherapy of rodent malaria, XXII. The value of drug-resistant strains of P. berghei in screening for blood schizontocidal activity. Ann Trop Med Parasitol 69: 155-171). All 20 studies were conducted according to the Guide for the Care and Use of Laboratory Animals (National-Research-Council. 1996. Guide for the Care and Use of Laboratory Animals. National Academy Press, Washington, DC) and PHS guidelines . The animals were maintained according to the NIH guidelines and allowed to acclimatize for 1 week before the start of the studies. On day 0, groups of Swiss female albino mice 4-6 weeks old (n = 5) were infected by injection into the tail vein with 0.2 ml of diluted heparinized blood to contain 1 x 107 25 N parasites -clone. The aminoindole analogs were formulated in 1.6% sodium salt mixed with lactic acid, 1% Tween 80, 9% ethanol and 20% Cerestar (hydroxypropyl-β-cyclodextrin; Wacker Chimie) and administered by probe Nasogastric oral On day 0, a single dose was administered 6 h after the initial infection, and during the subsequent 3 days the dose was divided and administered twice daily, with 6 hours between doses. Animals in the control group received vehicle alone. The dose concentration and dosage frequency was based on 30 preliminary tolerability / exposure studies. On day 4 after infection (5th day of trial), blood was collected by tail incision and microscopic slides were prepared and stained using Diff Quick®. Parasitized erythrocytes were counted and compared with the total number of erythrocytes per microscopic field to determine the percentage of parasitemia. A minimum of 350 erythrocytes was counted. Animals that show undetectable parasites on day 4 were examined every 2-3 days to determine if the cure was sterile. The

35 animals with parasites not detectable 28 days after cessation of the dosage (day 33 of the study) were considered cured.

The results (Table 4) show that the selected aminoindoles are highly active against P. berghei, suppressing parasitemia on the day of study 5 81-100%. Compound 3, compound 37, compound 142 and compound 267 were all able to affect cures at doses of 100-200 mg / kg / day.

Table 4: Effectiveness of aminoindoles against P. berghei

Compound

Dose (mg / kg / day) d.v.d. p.o. % suppression Day 5 Average day of recrudescence (number of animals / total) No. of cured

one

fifty 100% D13 (5/5) 0/5

2

fifty 80% NA 0/5

3

fifty 100% D12 (3/5) 2/5

100

100% NA 5/5

37

100 100% D17 (2/5) 3/5

200

100% NA 5/5

39

fifty 98% D10 (3/5) 0/5

100

99% D13 (3/5) 0/5

146

100 99% D6 (1/5) 0/5

202

100 95% NA 0/5

200

98% D17 (2/5) 0/5

142

100 99% D11 (1/5) 0/5

200

99% D13 (1/5) 3/5

266

100 81% NA 0/5

267

100 95% D14 (2/4) 0/5

200

100% D12 (2/5) 3/5

Legend of Table 4: Dose (mg / kg / day) d.v.d. p.o .: total daily dose in milligrams / kilogram administered orally in 2 divided doses / day; % of suppression Day 5: percentage reduction in parasitemia compared to 5 with the average of untreated controls on study day 5, approximately 17 h after the final dose. 100% suppression values indicate that no parasites were detected after microscopic examination; Animals can still contain parasites below the detection limit. Average day of recrudescence: animals that have undetectable parasites on day 5 had blood extensions examined every 2-3 days later until the parasites were observed again; the average of the day of the study in which the parasites 10 were detected again is recorded, preceded by the letter "D". The total number of animals with parasites not detectable on day 5, but which subsequently remitted, is provided as a proportion of the total number of animals in the dosage group (in brackets). NA: not applicable. Both all animals were parasitemic on day 5 and even all animals were cured. No. of cured: number of cured animals, as a proportion of all animals in the dosage group, defined as animals without detectable parasites at any time

15 until at least 30 days after cessation of dosing.

Efficacy in vivo against P. falciparum in mice:

Because rodent malaria species (such as P. berghei) are not necessarily identical to

20 human species (such as P. falciparum) with respect to sensitivity to antimalarial compounds, a "humanized mouse" model that supports the erythrocyte cycle of P. falciparum has been developed. Compound 267 was tested for efficacy against Pf3D70087 / N9 of P. falciparum which grows in NOD-scid IL-2Rulo mice grafted with human erythrocytes (Angulo-Barturen, I., et al. 2008. PLoS ONE 3: e2252) . Briefly, groups of 3 animals were infected on day 0 with 2 x 107 P. falciparum parasites and treated orally once a day for 4 days

25 with 5, 25 and 100 mg / kg / day formulated as described above starting on day 3 after infection. In parallel, groups of 3 animals were infected on day 0 with 1 x 107 parasites on day 0 and received the same doses starting 1 h after infection. Parasitemia was evaluated by FACS as previously described (Jiménez-Díaz, M.-B., et al. 2009. Cytometry Part A 75: 225-235). In the same humanized murine system, efficacy was also tested against P. berghei, with animals infected on day 0 (Jiménez-Díaz, M.

30 B., et al. 2005. Cytometry A 67: 27-36). The results are shown in Table 5.

Table 5. Efficacy of compound 267 in different rodent models

P. berghei N-clone

P. berghei ANKA strain GFP MRA-865 P. falciparum Pf3D70087 / N9

Compound No.

DE50 DE90 DE50 DE90 DE50 DE90

267 d.v.d ..

32 68 19 30 40 74

267 t.v.d.

35 58 ND ND ND ND

Legend of Table 5: Species and strains of parasites are listed above. DE50: Effective dose at which 50% of parasitemia is suppressed. Values were calculated by nonlinear regression analysis using GraphPad Prism and the units are in mg / kg / day. d.v.d: the animals were dosed twice a day; t.v.d .: the animals were dosed three times a day. Compound 267 was slightly more active against P. berghei than against P. falciparum, but the efficacy was very similar against both species of parasites.

5 The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.

Although the present invention has been shown and described particularly with references to exemplary embodiments thereof, it will be understood by those skilled in the art that various changes can be made in the form and details within it without departing from the scope of the invention encompassed by the appended claims.

Claims (17)

1. A compound of formula IIa: or a pharmaceutically acceptable salt thereof, in which: X is carbon or nitrogen; 10 Y is carbon or nitrogen; R1a is hydrogen, halogen, nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl ( C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R5a) 2, C (= NOH) NH2, NR5aCON (R5a) 2, WITH (R5a) 2, CO2R5a, COR6a, OC (O) R5a, SO2N (R5a) 2, SO2R6a, NR5aCOR6a, NR5aCO2R6a, NR5aSO2R6a or OC (= O) N (R5a) 2, 15 each optionally substituted with one or more groups represented by R4a; R2a is (C1-C6) alkyl, (C1-C6) alkoxy, S-C1-C6 alkyl, SO-C1-C6 alkyl or SO2-C1-C6 alkyl, optionally substituted with one or more groups represented by R4a; R3a is halogen, (C1-C6) alkyl or (C1-C6) alkoxy, each optionally substituted with one or more groups represented by R4a; Each R4a is independently halogen, nitro, cyano, hydroxy, (C1-C4) alkyl, halo (C1-C3) alkyl, hydroxyalkyl (C1-C4), alkoxy (C1-C4), haloalkoxy (C1-C4), aryl, haloaryl, cycloalkyl, aryl (C1-C3) alkyl, arylalkoxy (C1-C4), heterocyclyl, N (R5a) 2, C (= NOH) NH2, NR5aCON (R5a) 2, CON (R5a) 2, CO2R5a, COR6a, OC (O) R5a, cycloalkyl, -O-heterocyclyl, adamantyl, OC (= O) N (R5a) 2, Each R5a is independently hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C6) alkyl, each optionally substituted with halogen, (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl , haloalkoxy (C1-C3), cyano or nitro; and each R6a is independently hydrogen, halogen, (C1-C10) alkyl, (C1-C10) alkoxy, (C1-C3) arylalkyl, cycloalkyl or (C1-C3) alkoxy, each optionally substituted with halogen, (C1-) alkoxy C3), (C1-C3) alkyl, Haloalkyl (C1-C3), haloalkoxy (C1-C3), cyano or nitro. 2. The compound of claim 1, wherein: 1) R1a is halogen, (C1-C4) alkyl or (C1-C4) alkoxy; or 2) R1a is halogen, (C1-C4) alkyl or (C1-C4) alkoxy and R2a is (C1-C6) alkoxy; or 3) R2a is (C1-C6) alkoxy; or 4) R1a is halogen, (C1-C4) alkoxy or (C1-C4) alkoxy and R2a is (C1-C6) alkoxy and R3a is halogen; or 5) R1a is halogen, (C1-C4) alkyl or (C1-C4) alkoxy and R3a is halogen, or 6) R3a is halogen. 3. The compound of claim 2, wherein: 1) R1a is chlorine, R2a is ethoxy, R3a is fluorine and X is carbon, or 2) R1a is chlorine, R2a and R3a are methoxy and X is nitrogen. Four. Five 4. The compound of any one of claims 1-3, represented by formula IIIa: or a pharmaceutically acceptable salt thereof. 5. A compound of formula VI: or a pharmaceutically acceptable salt thereof, in which: R1b is hydrogen, halogen, nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1 C6), aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R3b ) 2, C (= NOH) NH2, NR3CON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3b, SO2N (R3b) 2, SO2R4b, NR3COR4b, NR3bCO2R4b, NR3bSO2R4b or OC (= O ) N (R3b) 2, each optionally substituted with one or more groups represented by R2b; each R2b is independently halogen, nitro, cyano, hydroxy, (C1-C4) alkyl, halo (C1-C3) alkyl, Hydroxyalkyl (C1-C4), alkoxy (C1-C4), haloalkoxy (C1-C4), aryl, haloaryl, cycloalkyl, arylalkyl (C1-C3), arylalkoxy (C1-C4), heterocyclyl, N (R3b) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3b, cycloalkyl, -O-heterocyclyl, adamantyl, OC (= O) N (R3b) 2, Each R3b is independently hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C3) alkyl, each optionally substituted with halogen, (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl , haloalkoxy (C1-C3), cyano or nitro; and each R4b is independently hydrogen, halogen, (C1-C10) alkyl, (C1-C10) alkoxy, aryl, aryl (C1-C3) alkyl, cycloalkyl or arylalkoxy (C1-C3), each optionally substituted with halogen, alkoxy ( C1-C3), alkyl (C1-C3), haloalkyl (C1-C3), haloalkoxy (C1-C3), cyano or nitro. 6. The compound of claim 5, wherein: 1) R1b is halogen, (C1-C6) alkyl or (C1-C6) alkoxy; or 2) R1b is halogen; or 10 3) R1b is chloro, methyl or methoxy. 7. A pharmaceutical composition comprising the compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A compound of formula I: or a pharmaceutically acceptable salt thereof, in which: R1, R2, R3 and R4 are independently hydrogen, halogen, nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), -N (R7) 2, C ( = NOH) NH2, -NR7CON (R7) 2, -CON (R7) 2, -CO2R7, -COR8, -OC (O) R7, -SO2N (R7) 2, -SO2R8, -NR7COR8, NR7CO2R8, -NR7SO2R8 or -OC (= O) N (R7) 2, each optionally substituted with one or more groups represented by R6; wherein R2 and R3, together with the carbons to which they are attached, can form a heterocyclyl or heteroaryl, in which the heterocyclyl or heteroaryl formed is optionally substituted with one or more groups represented by R6; R5 is aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl (C1-C3), arylheterocyclyl (C3-C10), arylalkoxy (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclyl-alkyl (C1-C3) C3), alkylheteroaryl, (C1-C6) alkyl, or (C1-C4) alkoxy, each optionally substituted with one to three groups represented by R6; each R6 is independently halogen, nitro, cyano, hydroxy, (C1-C4) alkyl, halo (C1-C3) alkyl, hydroxyalkyl (C1-C4), alkoxy (C1-C4), haloalkoxy (C1-C4), aryl, haloaryl , cycloalkyl, aryl (C1-C3) alkyl, arylalkoxy 35 (C1-C4), heterocyclyl, -N (R7) 2, -C (= NOH) NH2, -NR7CON (R7) 2, -CON (R7) 2, -CO2R7, -COR8, -OC (O) R8 , cycloalkyl, -O-heterocyclyl, adamantyl, -OC (= O) N (R7) 2, each R7 is independently hydrogen, (C1-C10) alkyl, aryl or arylalkyl (C1-C3), each optionally substituted with halogen, (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, halo (C1-C3) haloalkoxy, cyano or nitro; Y Each R8 is independently hydrogen, halogen, (C1-C10) alkyl, (C1-C10) alkoxy, aryl, aryl (C1-C3) alkyl, cycloalkyl or arylalkoxy (C1-C3), each optionally substituted with halogen, alkoxy ( C1-C3), alkyl (C1-C3), haloalkyl (C1-C3), haloalkoxy (C1-C3), cyano or nitro; or a compound of formula II: or a pharmaceutically acceptable salt thereof, in which: X is carbon or nitrogen; 5 Y is carbon or nitrogen; R1, R2 and R3 are independently hydrogen, halogen, nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, aryl, heteroaryl, cycloalkyl , heterocyclyl, aryl (C1-C3) alkyl, heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), -N (R7) 2, C (= NOH) NH2, -NR7CON (R7) 2, -CON (R7) 2, -CO2R7, -COR8, -OC (O) R7, -SO2N (R7) 2, -SO2R8, -NR7COR8, NR7CO2R8, -NR7SO2R8 or -OC (= O) N (R7) 2, each optionally substituted with one or more groups represented by R6; each R6 is independently halogen, nitro, cyano, hydroxy, (C1-C4) alkyl, halo (C1-C3) alkyl, hydroxyalkyl (C1-C4), alkoxy (C1-C4), haloalkoxy (C1-C4), aryl, haloaryl , cycloalkyl, aryl (C1-C3) alkyl, arylalkoxy (C1-C4), heterocyclyl, -N (R7) 2, -C (= NOH) NH2, -NR7CON (R7) 2, -CON (R7) 2, -CO2R7 , -CO R8, -OC (O) R8, 15 SO2N (R8) 2, -SO2R8, -SR8, -S-alkyl (C1-C3) -cycloalkyl, -NR7COR8, -NR7CO2R8, -NR8SO2R8, -S (= O) R8, -O cycloalkyl, -O-heterocyclyl, adamantyl, -OC (= O) N (R7) 2, each R7 is independently hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C3) alkyl, each optionally substituted by halogen, (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, halo (C1-C3) haloalkoxy, cyano or nitro; Y each R8 is independently hydrogen, halogen, (C1-C10) alkyl, (C1-C10) alkoxy, aryl, aryl (C1-C3) alkyl, Cycloalkyl or arylalkoxy (C1-C3), each optionally substituted with halogen, (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3), haloalkoxy (C1-C3), cyano or nitro for its Use in the treatment of malaria. 9. The compound of claim 8, wherein the compound is a compound of formula I, or a pharmaceutically acceptable salt thereof, and: 1) R1, R2, R3 and R4 are independently hydrogen, halogen, (C1-C4) alkyl or (C1-C4) alkoxy, or 2) R1, R2 and R4 are independently hydrogen, halogen, (C1-C4) alkyl or (C1-C4) alkoxy, and R3 is chlorine, or 3) R3 is chlorine. 10. The compound of claim 8, wherein the compound is a compound of formula II: 35 or a pharmaceutically acceptable salt thereof, in which: X is carbon or nitrogen; Y is carbon or nitrogen; R1, R2 and R3 are independently hydrogen, halogen, nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-) alkenyl C6), (C1-C6) alkynyl, (C1-C6) alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, aryl (C1-C3) alkyl, heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), -N (R7) 2, 5 C (= NOH) NH2, -NR7CON (R7) 2, -CON (R7) 2, -CO2R7, -COR8, -OC (O) R7, -SO2N (R7) 2, -SO2R8, -NR7COR8, -NR7CO2R8 , -NR7SO2R8 or -OC (= O) N (R7) 2, each optionally substituted with one or more groups represented by R6; each R6 is independently halogen, nitro, cyano, hydroxy, (C1-C4) alkyl, halo (C1-C3) alkyl, hydroxyalkyl (C1-C4), alkoxy (C1-C4), haloalkoxy (C1-C4), aryl, haloaryl , cycloalkyl, aryl (C1-C3) alkyl, arylalkoxy 10 (C1-C4), heterocyclyl, -N (R7) 2, -C (= NOH) NH2, -NR7CON (R7) 2, -CON (R7) 2, -CO2R7, -COR8, -OC (O) R8 , -SO2N (R8) 2, -SO2R8, -SR8, -S-alkyl (C1-C3) -cycloalkyl, -NR7COR8, -NR7CO2R8, -NR8SO2R8, -S (= O) R8, -O cycloalkyl; -O-heterocyclyl, adamantyl, -OC (= O) N (R7) 2, each R7 is independently hydrogen, (C1-C10) alkyl, aryl or arylalkyl (C1-C3), each optionally substituted with halogen, alkoxy ( C1-C3), alkyl (C1-C3), haloalkyl (C1-C3), haloalkoxy (C1-C3), cyano or nitro; Y Each R8 is independently hydrogen, halogen, (C1-C10) alkyl, (C1-C10) alkoxy, aryl, aryl (C1-C3) alkyl, cycloalkyl or arylalkoxy (C1-C3), each optionally substituted with halogen, alkoxy ( C1-C3), alkyl (C1-C3), haloalkyl (C1-C3), haloalkoxy (C1-C3), cyano or nitro. 11. The compound of claim 10, wherein: 1) R1 is chlorine, R2 is ethoxy, R3 is fluorine, X is carbon and Y is carbon; or 2) R1 is chlorine, R2 and R3 are methoxy, X is nitrogen and Y is carbon; or 3) R1 is chlorine, R2 is hydroxy and R3 is fluorine; or 4) R1 is chlorine, R2 is hydroxyl, R3 is fluorine, X is carbon and Y is carbon. 12. The compound of claim 10, wherein the compound is a compound of formula III: 30 or formula XXIII: or a pharmaceutically acceptable salt thereof, in which: 1) R1, R2 and R3 are as set forth in claim 10, or 2) R1 is chlorine, R2 is ethoxy, R3 is fluorine, X is carbon and Y is carbon; or 3) R1 is chlorine, R2 is hydroxy and R3 is fluorine; or 13. A method of preparing a compound represented by formula VII: or a pharmaceutically acceptable salt thereof, in which: each R1b is independently hydrogen, halogen, nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, 10 (C1-C6) alkynyl, (C1-C6) alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclyl (C1-C3) alkyl , hydroxyalkyl (C1-C3), N (R3b) 2, C (= NOH) NH2, NR3CON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3b, SO2N (R3b) 2, SO2R4b , NR3COR4b, NR3CO2R4b, NR3SO2R4b or OC (= O) N (R3) 2, each optionally substituted with one or more groups represented by R2b; each R2b is independently halogen, nitro, cyano, hydroxy, (C1-C4) alkyl, halo (C1-C3) alkyl, Hydroxyalkyl (C1-C4), alkoxy (C1-C4), haloalkoxy (C1-C4), aryl, haloaryl, cycloalkyl, arylalkyl (C1-C3), arylalkoxy (C1-C4), heterocyclyl, N (R3b) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3b, cycloalkyl, -O-heterocyclyl, adamantyl, OC (= O) N (R3b) 2, Each R3b is independently hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C3) alkyl, each optionally substituted with halogen, (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl , haloalkoxy (C1-C3), cyano or nitro; and each R4b is independently hydrogen, halogen, (C1-C10) alkyl, (C1-C10) alkoxy, aryl, aryl (C1-C3) alkyl, cycloalkyl or arylalkoxy (C1-C3), each optionally substituted with halogen, alkoxy ( C1-C3), alkyl (C1-C3), haloalkyl (C1-C3), haloalkoxy (C1-C3), cyano or nitro, 25 comprising the method: a) reacting a compound represented by formula VIII: wherein R1b is defined as before, with an agent represented by formula IX: in which R2b is defined as before and M is -MgBr, -Li or -B (OH) 2, thus forming a compound represented by the formula X: wherein R1b and R2b are defined as before; Y b) aminating the compound of formula X with tert-butyldimethylsilylamine in the presence of SnCl4 and an agent selected from the group consisting of triethylamine, N-ethyldiisopropylamine and N-methylmorpholine, thus forming the compound represented by formula VII, or a pharmaceutically acceptable salt thereof. 14. A method of preparing a compound represented by formula XI: or a pharmaceutically acceptable salt thereof, in which: Each R1b is independently hydrogen, halogen, nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl , arylalkyl (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R3b) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3b, SO2N (R3b) 2, SO2R4b NR3bCOR4b, NR3CO2R4b, NR3SO2R4b or OC (= O) N (R3b) 2, each optionally substituted with one or more groups represented by R2b; Each R2b is independently halogen, nitro, cyano, hydroxy, (C1-C4) alkyl, halo (C1-C3) alkyl, hydroxyalkyl (C1-C4), alkoxy (C1-C4), haloalkoxy (C1-C4), aryl, haloaryl, cycloalkyl, aryl (C1-C3) alkyl, arylalkoxy (C1-C4), heterocyclyl, N (R3b) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3b, SO2N (R3b) 2, SO2R4b, SR4b, S-(C1-C3) alkylcycloalkyl, NR3bCOR4b, NR3bCO2R4b, NR3bSO2R4b, S (= O) R3b, -Ocycloalkyl, -O-heterocyclyl, adamantyl, OC (= O) N (R3b) 2, each R3b is independently hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C3) alkyl, each optionally substituted with halogen, (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, haloalkoxy (C1-C3), cyano or nitro; Y Each R4b is independently hydrogen, halogen, (C1-C10) alkyl, (C1-C10) alkoxy, aryl, aryl (C1-C3) alkyl, cycloalkyl or arylalkoxy (C1-C3), each optionally substituted with halogen, alkoxy ( C1-C3), alkyl (C1-C3), haloalkyl (C1-C3), haloalkoxy (C1-C3), cyano or nitro, the method comprising: 10 a) reacting a compound represented by formula XII: in which R1b is defined as before; with an agent represented by formula XIII: in which R2b is defined as before; thus forming a compound represented by the formula XIV: wherein R1b and R2b are defined as before; and b) reacting the compound of formula XIV with H2 in the presence of Pd / C and, optionally, diphenyl sulfide, thus forming the compound represented by formula XV: wherein R1b and R2b are defined as before; and c) oxidizing the compound of formula XV with potassium peroximonosulfate, thus forming a compound represented by formula XVI: wherein R1b and R2b are defined as before; Y d) aminating the compound of formula XVI with tert-butyldimethylsilylamine in the presence of SnCl4 and an agent selected from the group consisting of triethylamine, N-ethyldiisopropylamine and N-methylmorpholine, thus forming the compound represented by formula XI, or a pharmaceutically acceptable salt thereof. 15. A method of preparing a compound represented by formula XVII: or a pharmaceutically acceptable salt thereof, in which: Each R1b is independently hydrogen, halogen, nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl , arylalkyl (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R3b) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3, SO2N (R3b) 2, SO2R4b, NR3COR4, NR3bCO2R4b, NR3bSO2R4b or OC (= O) N (R3b) 2, each optionally substituted with one or more groups represented by R2b; each R2b is independently halogen, nitro, cyano, hydroxy, (C1-C4) alkyl, halo (C1-C3) alkyl, hydroxyalkyl (C1-C4), alkoxy (C1-C4), haloalkoxy (C1-C4), aryl, haloaryl , cycloalkyl, arylalkyl (C1-C3), arylalkoxy (C1-C4), heterocyclyl, N (R3b) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC ( O) R3b, S, SO2N (R3b) 2, SO2R4b, SR4b, S-(C1-C3) alkylcycloalkyl, NR3bCOR4b, NR3bCO2R4b, NR3bSO2R4b, S (= O) R3b, -Ocycloalkyl, -O-heterocyclyl, OC (= O) N (R3) 2, each R3b is independently hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C3) alkyl, each optionally substituted with halogen, (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, haloalkoxy (C1-C3), cyano or nitro; Y Each R4b is independently hydrogen, halogen, (C1-C10) alkyl, (C1-C10) alkoxy, aryl, aryl (C1-C3) alkyl, cycloalkyl or arylalkoxy (C1-C3), each optionally substituted with halogen, alkoxy ( C1-C3), alkyl (C1-C3), haloalkyl (C1-C3), haloalkoxy (C1-C3), cyano or nitro, the method comprising: 10 a) reducing a compound represented by formula XVIII: in which R1b is defined as before, with triethylsilane and trifluoroacetic acid, thus forming a compound represented by the formula XIX: in which R1b is defined as before; Y b) oxidize the compound of formula XIX with an agent represented by formula XX: in the presence of potassium hexamethyldisilazane and tetrahydrofuran, thus forming a compound represented by the formula XXI: in which R1b is defined as before; Y c) aminating the compound of formula XXI with tert-butyldimethylsilylamine in the presence of SnCl4 and an agent 5 selected from triethylamine, N-ethyldiisopropylamine and N-methylmorpholine, thus forming the compound represented by the formula (XVII), or a pharmaceutically acceptable salt thereof. 16. A method of preparing a compound represented by formula VII: 10 or a pharmaceutically acceptable salt thereof, in which: Each R1b is independently hydrogen, halogen, nitro, cyano, hydroxy, (C1-C6) alkyl, (C1-C6) alkenyl, (C1-C6) alkynyl, (C1-C6) alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl , arylalkyl (C1-C3), heteroarylalkyl (C1-C3), cycloalkylalkyl (C1-C3), heterocyclylalkyl (C1-C3), hydroxyalkyl (C1-C3), N (R3b) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC (O) R3, SO2N (R3b) 2, SO2R4b, NR3COR4, NR3bCO2R4b, NR3bSO2R4b or OC (= O) N (R3b) 2, each optionally substituted with one or more groups represented by R2b; each R2b is independently halogen, nitro, cyano, hydroxy, (C1-C4) alkyl, halo (C1-C3) alkyl, hydroxyalkyl (C1-C4), alkoxy (C1-C4), haloalkoxy (C1-C4), aryl, haloaryl , cycloalkyl, arylalkyl (C1-C3), arylalkoxy (C1-C4), heterocyclyl, N (R3b) 2, C (= NOH) NH2, NR3bCON (R3b) 2, CON (R3b) 2, CO2R3b, COR4b, OC ( O) R3b, S, Cycloalkyl, -O-heterocyclyl, adamantyl, OC (= O) N (R3) 2, each R3b is independently hydrogen, (C1-C10) alkyl, aryl or aryl (C1-C3) alkyl, each optionally substituted with halogen, (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3) alkyl, haloalkoxy (C1-C3), cyano or nitro; and each R4b is independently hydrogen, halogen, (C1-C10) alkyl, (C1-C10) alkoxy, aryl, aryl (C1-C3) alkyl, Cycloalkyl or arylalkoxy (C1-C3), each optionally substituted with halogen, (C1-C3) alkoxy, (C1-C3) alkyl, halo (C1-C3), haloalkoxy (C1-C3), cyano or nitro; and R5b is hydrogen or C (= O) O (C1-C3) alkyl, the method comprising: aminating a compound represented by formula X: wherein R1b and R2b are defined as before; with tert-butyldimethylsilylamine in the presence of SnCl4 and an agent selected from the group consisting of 5 triethylamine, N-ethyldiisopropylamine and N-methylmorpholine, thus forming the compound represented by formula VII, or a pharmaceutically acceptable salt thereof. 17. The method of claim 16, wherein the compound represented by formula VII has the structure of formula XVII: or a pharmaceutically acceptable salt thereof; and the method comprises: aminating a compound represented by formula XXI: 20 with tert-butyldimethylsilylamine in the presence of SnCl4 and an agent selected from the group consisting of triethylamine, N-ethyldiisopropylamine and N-methylmorpholine, thus forming the compound represented by formula XVII, or a pharmaceutically acceptable salt thereof. 18. The compound of claim 8, wherein the compound is represented by the following structural formula: or a pharmaceutically acceptable salt thereof.